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Oh KW, Kim DK, Hsu AL, Lee SJ. Distinct sets of lysosomal genes define synucleinopathy and tauopathy. BMB Rep 2023; 56:657-662. [PMID: 37817435 PMCID: PMC10761752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Revised: 08/23/2023] [Accepted: 09/11/2023] [Indexed: 10/12/2023] Open
Abstract
Neurodegenerative diseases are characterized by distinct protein aggregates, such as those of α-synuclein and tau. Lysosomal defect is a key contributor to the accumulation and propagation of aberrant protein aggregates in these diseases. The discoveries of common proteinopathies in multiple forms of lysosomal storage diseases (LSDs) and the identification of some LSD genes as susceptible genes for those proteinopathies suggest causative links between LSDs and the proteinopathies. The present study hypothesized that defects in lysosomal genes will differentially affect the propagation of α-synuclein and tau proteins, thereby determining the progression of a specific proteinopathy. We established an imaging-based high-contents screening (HCS) system in Caenorhabditis elegans (C. elegans) model, by which the propagation of α-synuclein or tau is measured by fluorescence intensity. Using this system, we performed RNA interference (RNAi) screening to induce a wide range of lysosomal malfunction through knock down of 79 LSD genes, and to obtain the candidate genes with significant change in protein propagation. While some LSD genes commonly affected both α-synuclein and tau propagation, our study identified the distinct sets of LSD genes that differentially regulate the propagation of either α-synuclein or tau. The specificity and efficacy of these LSD genes were retained in the disease-related phenotypes, such as pharyngeal pumping behavior and life span. This study suggests that distinct lysosomal genes differentially regulate the propagation of α-synuclein and tau, and offer a steppingstone to understanding disease specificity. [BMB Reports 2023; 56(12): 657-662].
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Affiliation(s)
- Kyu Won Oh
- Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea, Seoul 04796, Korea
| | - Dong-Kyu Kim
- Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea, Seoul 04796, Korea
| | - Ao-Lin Hsu
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 112-304, Taiwan, Seoul 04796, Korea
| | - Seung-Jae Lee
- Department of Biomedical Sciences, Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea, Seoul 04796, Korea
- Convergence Research Center for Dementia, Seoul National University College of Medicine, Seoul 03081, Korea
- Neuramedy Co. Ltd., Seoul 04796, Korea
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2
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Corraliza-Gomez M, Bermejo T, Lilue J, Rodriguez-Iglesias N, Valero J, Cozar-Castellano I, Arranz E, Sanchez D, Ganfornina MD. Insulin-degrading enzyme (IDE) as a modulator of microglial phenotypes in the context of Alzheimer's disease and brain aging. J Neuroinflammation 2023; 20:233. [PMID: 37817156 PMCID: PMC10566021 DOI: 10.1186/s12974-023-02914-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/28/2023] [Indexed: 10/12/2023] Open
Abstract
The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.
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Affiliation(s)
- Miriam Corraliza-Gomez
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain.
| | - Teresa Bermejo
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain
| | | | - Noelia Rodriguez-Iglesias
- Achucarro Basque Center for Neuroscience, Science Park of the UPV/EHU, Leioa, Spain
- Department of Neurosciences, University of the Basque Country, Leioa, Spain
| | - Jorge Valero
- Institute of Neuroscience of Castilla y León-INCyL, University of Salamanca, Salamanca, Spain
- Institute for Biomedical Research of Salamanca, Salamanca, Spain
| | - Irene Cozar-Castellano
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Eduardo Arranz
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain
| | - Diego Sanchez
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain
| | - Maria Dolores Ganfornina
- Instituto de Biomedicina y Genética Molecular, Excellence Unit, University of Valladolid-CSIC, Valladolid, Spain
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Zhang L, Cao J, Yang H, Pham P, Khan U, Brown B, Wang Y, Zieneldien T, Cao C. Commercial and Instant Coffees Effectively Lower Aβ1-40 and Aβ1-42 in N2a/APPswe Cells. Front Nutr 2022; 9:850523. [PMID: 35369094 PMCID: PMC8965317 DOI: 10.3389/fnut.2022.850523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 02/08/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alzheimer's disease (AD) is a multifactorial neurological disease with neurofibrillary tangles and neuritic plaques as histopathological markers. Due to this, although AD is the leading cause of dementia worldwide, clinical AD dementia cannot be certainly diagnosed until neuropathological post-mortem evaluation. Coffee has been reported to have neurologically protective factors, particularly against AD, but coffee brand and type have not been taken into consideration in previous studies. We examined the discrepancies among popular commercial and instant coffees in limiting the development and progression through Aβ1-40 and Aβ1-42 production, and hypothesized that coffee consumption, regardless of brand or type, is beneficial for stalling the progression and development of Aβ-related AD. Methods Coffee samples from four commercial coffee brands and four instant coffees were purchased or prepared following given instructions and filtered for the study. 5, 2.5, and 1.25% concentrations of each coffee were used to treat N2a/APPswe cell lines. MTT assay was used to assess cell viability for coffee concentrations, as well as pure caffeine concentrations. Sandwich ELISA assay was used to determine Aβ concentration for Aβ1-40 and Aβ1-42 peptides of coffee-treated cells. Results Caffeine concentrations were significantly varied among all coffees (DC vs. MDC, PC, SB, NIN, MIN p < 0.05). There was no correlation between caffeine concentration and cell toxicity among brands and types of coffee, with no toxicity at 0.5 mg/ml caffeine and lower. Most coffees were toxic to N2a/APPswe cells at 5% (p < 0.05), but not at 2.5%. Most coffees at a 2.5% concentration reduced Aβ1-40 and Aβ1-42 production, with comparable results between commercial and instant coffees. Conclusion All coffees tested have beneficial health effects for AD through lowering Aβ1-40 and Aβ1-42 production, with Dunkin' Donuts® medium roast coffee demonstrating the most consistent and optimal cell survival rates and Aβ concentration. On the other hand, Starbucks® coffee exhibited the highest cell toxicity rates among the tested coffees.
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Affiliation(s)
- Lifang Zhang
- Department of Neurological Rehabilitation, The Affiliated Brain Hospital of Guangzhou Medical University, Guanzhou, China
| | - Jessica Cao
- Department of Kinesiology, Wiess School of Natural Sciences, Rice University, Houston, TX, United States
| | - Haiqiang Yang
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Phillip Pham
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Umer Khan
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Breanna Brown
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Yanhong Wang
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Tarek Zieneldien
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
| | - Chuanhai Cao
- Department of Pharmaceutical Sciences, Taneja College of Pharmacy, University of South Florida, Tampa, FL, United States
- Department of Neurology, College of Medicine, University of South Florida, Tampa, FL, United States
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Yoo SY, Han A, Park S, Lee JY. Incidence and Cognitive Decline of Alzheimer's Disease and Other Dementia by Apolipoprotein ε4 Allele Presence: A Community-Based Cohort Study in Korean Elderly. Psychiatry Investig 2022; 19:190-196. [PMID: 35232006 PMCID: PMC8958210 DOI: 10.30773/pi.2021.0347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Accepted: 11/24/2021] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVE This study aimed to investigate the role of apolipoprotein E (APOE) ε4 allele to the incidence of dementia and cognitive decline in a cohort of a Korean community. METHODS From a community-based dementia-free cohort, 357 participants were genotyped. Participants underwent 2 cognitive assessments separated by a hiatus between 6 to 7 years and were diagnosed as healthy control (n=297), Alzheimer's disease (AD) (n=44), and other dementia (n=16) at the second assessment. Incidence risk and onset age of disease according to APOE ε4 presence were analyzed in AD and other dementia. Differences in cognitive decline rate depending on APOE ε4 were also examined across all groups. RESULTS The relative risks and onset age of dementia were not different by the presence of the APOE ε4 allele. Cognitive decline was more prominent in the presence of APOE ε4 allele (score change=7.4) than non-presence (score change=3.1), and this interaction was significant only in the AD group (F=10.51, p=0.003). CONCLUSION The APOE ε4 alleles can be a critical factor in predicting cognitive change for AD in the Korean community population but not in predicting AD incidence. This finding suggest that clinicians consider the presence of APOE ε4 allele examining patients with rapid declining dementia.
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Affiliation(s)
- So Young Yoo
- Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea
| | - Alexander Han
- Department of BioSciences & Department of Statistics, Rice University, Houston, TX, USA
| | - Soowon Park
- Division of Teacher Education, College of General Education for Truth, Sincerity and Love, Kyonggi University, Suwon, Republic of Korea
| | - Jun-Young Lee
- Department of Psychiatry, SMG-SNU Boramae Medical Center, Seoul, Republic of Korea.,Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
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Szu JI, Obenaus A. Cerebrovascular phenotypes in mouse models of Alzheimer's disease. J Cereb Blood Flow Metab 2021; 41:1821-1841. [PMID: 33557692 PMCID: PMC8327123 DOI: 10.1177/0271678x21992462] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 12/16/2020] [Accepted: 01/06/2021] [Indexed: 12/12/2022]
Abstract
Alzheimer's disease (AD) is a devastating neurological degenerative disorder and is the most common cause of dementia in the elderly. Clinically, AD manifests with memory and cognitive decline associated with deposition of hallmark amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs). Although the mechanisms underlying AD remains unclear, two hypotheses have been proposed. The established amyloid hypothesis states that Aβ accumulation is the basis of AD and leads to formation of NFTs. In contrast, the two-hit vascular hypothesis suggests that early vascular damage leads to increased accumulation of Aβ deposits in the brain. Multiple studies have reported significant morphological changes of the cerebrovasculature which can result in severe functional deficits. In this review, we delve into known structural and functional vascular alterations in various mouse models of AD and the cellular and molecular constituents that influence these changes to further disease progression. Many studies shed light on the direct impact of Aβ on the cerebrovasculature and how it is disrupted during the progression of AD. However, more research directed towards an improved understanding of how the cerebrovasculature is modified over the time course of AD is needed prior to developing future interventional strategies.
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Affiliation(s)
- Jenny I Szu
- Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA, USA
| | - André Obenaus
- Department of Pediatrics, University of California Irvine, Irvine, CA, USA
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6
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Cho S, Lee H, Seo J. Impact of Genetic Risk Factors for Alzheimer's Disease on Brain Glucose Metabolism. Mol Neurobiol 2021; 58:2608-2619. [PMID: 33479841 DOI: 10.1007/s12035-021-02297-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/13/2021] [Indexed: 12/14/2022]
Abstract
Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 30 million people worldwide. Despite growing knowledge of AD pathophysiology, a complete understanding of the pathogenic mechanisms underpinning AD is lacking, and there is currently no cure for AD. Extant literature suggests that AD is a polygenic and multifactorial disease underscored by complex and dynamic pathogenic mechanisms. Despite extensive research and clinical trials, there has been a dearth of novel drugs for AD treatment on the market since memantine in 2003. This lack of therapeutic success has directed the entire research community to approach the disease from a different angle. In this review, we discuss growing evidence for the close link between altered glucose metabolism and AD pathogenesis by exploring how genetic risk factors for AD are associated with dysfunctional glucose metabolism. We also discuss modification of genes responsible for metabolic pathways implicated in AD pathology.
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Affiliation(s)
- Sukhee Cho
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea
| | - Hyein Lee
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea
| | - Jinsoo Seo
- Department of Brain and Cognitive Sciences, DGIST, Daegu, 42988, South Korea.
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7
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Sun BL, Chen Y, Fan DY, Zhu C, Zeng F, Wang YJ. Critical thinking on amyloid-beta-targeted therapy: challenges and perspectives. SCIENCE CHINA-LIFE SCIENCES 2020; 64:926-937. [DOI: 10.1007/s11427-020-1810-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/28/2020] [Indexed: 01/02/2023]
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Hawkins KE, Duchen M. Modelling mitochondrial dysfunction in Alzheimer’s disease using human induced pluripotent stem cells. World J Stem Cells 2019; 11:236-253. [PMID: 31171953 PMCID: PMC6545525 DOI: 10.4252/wjsc.v11.i5.236] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/22/2019] [Accepted: 03/26/2019] [Indexed: 02/06/2023] Open
Abstract
Alzheimer’s disease (AD) is the most common form of dementia. To date, only five pharmacological agents have been approved by the Food and Drug Administration for clinical use in AD, all of which target the symptoms of the disease rather than the cause. Increasing our understanding of the underlying pathophysiology of AD will facilitate the development of new therapeutic strategies. Over the years, the major hypotheses of AD etiology have focused on deposition of amyloid beta and mitochondrial dysfunction. In this review we highlight the potential of experimental model systems based on human induced pluripotent stem cells (iPSCs) to provide novel insights into the cellular pathophysiology underlying neurodegeneration in AD. Whilst Down syndrome and familial AD iPSC models faithfully reproduce features of AD such as accumulation of Aβ and tau, oxidative stress and mitochondrial dysfunction, sporadic AD is much more difficult to model in this way due to its complex etiology. Nevertheless, iPSC-based modelling of AD has provided invaluable insights into the underlying pathophysiology of the disease, and has a huge potential for use as a platform for drug discovery.
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Affiliation(s)
- Kate Elizabeth Hawkins
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
| | - Michael Duchen
- Cell and Developmental Biology, Division of Biosciences, University College London, London WC1E 6BT, United Kingdom
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9
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Stefanidis L, Fusco ND, Cooper SE, Smith-Carpenter JE, Alper BJ. Molecular Determinants of Substrate Specificity in Human Insulin-Degrading Enzyme. Biochemistry 2018; 57:4903-4914. [PMID: 30004674 DOI: 10.1021/acs.biochem.8b00474] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Insulin-degrading enzyme (IDE) is a 110 kDa chambered zinc metalloendopeptidase that degrades insulin, amyloid β, and other intermediate-sized aggregation prone peptides that adopt β-structures. Structural studies of IDE in complex with multiple physiological substrates have suggested a role for hydrophobic and aromatic residues of the IDE active site in substrate binding and catalysis. Here, we examine functional requirements for conserved hydrophobic and aromatic IDE active site residues that are positioned within 4.5 Å of IDE-bound insulin B chain and amyloid β peptides in the reported crystal structures for the respective enzyme-substrate complexes. Charge, size, hydrophobicity, aromaticity, and other functional group requirements for substrate binding IDE active site residues were examined through mutational analysis of the recombinant human enzyme and enzyme kinetic studies conducted using native and fluorogenic derivatives of human insulin and amyloid β peptides. A functional requirement for IDE active site residues F115, A140, F141, Y150, W199, F202, F820, and Y831 was established, and specific contributions of residue charge, size, and hydrophobicity to substrate binding, specificity, and proteolysis were demonstrated. IDE mutant alleles that exhibited enhanced or diminished proteolytic activity toward insulin or amyloid β peptides and derivative substrates were identified.
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Affiliation(s)
- Lazaros Stefanidis
- Department of Chemistry , Sacred Heart University , Fairfield , Connecticut 06825 , United States
| | - Nicholas D Fusco
- Department of Chemistry , Sacred Heart University , Fairfield , Connecticut 06825 , United States
| | - Samantha E Cooper
- Department of Chemistry and Biochemistry , Fairfield University , Fairfield , Connecticut 06824 , United States
| | - Jillian E Smith-Carpenter
- Department of Chemistry and Biochemistry , Fairfield University , Fairfield , Connecticut 06824 , United States
| | - Benjamin J Alper
- Department of Chemistry , Sacred Heart University , Fairfield , Connecticut 06825 , United States
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10
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Akan I, Olivier-Van Stichelen S, Bond MR, Hanover JA. Nutrient-driven O-GlcNAc in proteostasis and neurodegeneration. J Neurochem 2017; 144:7-34. [PMID: 29049853 DOI: 10.1111/jnc.14242] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Revised: 09/28/2017] [Accepted: 10/11/2017] [Indexed: 12/14/2022]
Abstract
Proteostasis is essential in the mammalian brain where post-mitotic cells must function for decades to maintain synaptic contacts and memory. The brain is dependent on glucose and other metabolites for proper function and is spared from metabolic deficits even during starvation. In this review, we outline how the nutrient-sensitive nucleocytoplasmic post-translational modification O-linked N-acetylglucosamine (O-GlcNAc) regulates protein homeostasis. The O-GlcNAc modification is highly abundant in the mammalian brain and has been linked to proteopathies, including neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's. C. elegans, Drosophila, and mouse models harboring O-GlcNAc transferase- and O-GlcNAcase-knockout alleles have helped define the role O-GlcNAc plays in development as well as age-associated neurodegenerative disease. These enzymes add and remove the single monosaccharide from protein serine and threonine residues, respectively. Blocking O-GlcNAc cycling is detrimental to mammalian brain development and interferes with neurogenesis, neural migration, and proteostasis. Findings in C. elegans and Drosophila model systems indicate that the dynamic turnover of O-GlcNAc is critical for maintaining levels of key transcriptional regulators responsible for neurodevelopment cell fate decisions. In addition, pathways of autophagy and proteasomal degradation depend on a transcriptional network that is also reliant on O-GlcNAc cycling. Like the quality control system in the endoplasmic reticulum which uses a 'mannose timer' to monitor protein folding, we propose that cytoplasmic proteostasis relies on an 'O-GlcNAc timer' to help regulate the lifetime and fate of nuclear and cytoplasmic proteins. O-GlcNAc-dependent developmental alterations impact metabolism and growth of the developing mouse embryo and persist into adulthood. Brain-selective knockout mouse models will be an important tool for understanding the role of O-GlcNAc in the physiology of the brain and its susceptibility to neurodegenerative injury.
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Affiliation(s)
- Ilhan Akan
- Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland, USA
| | | | - Michelle R Bond
- Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland, USA
| | - John A Hanover
- Laboratory of Cell and Molecular Biology, NIDDK, National Institutes of Health, Bethesda, Maryland, USA
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AnkG hemizygous mice present cognitive impairment and elevated anxiety/depressive-like traits associated with decreased expression of GABA receptors and postsynaptic density protein. Exp Brain Res 2017; 235:3375-3390. [PMID: 28821923 DOI: 10.1007/s00221-017-5056-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 08/03/2017] [Indexed: 10/19/2022]
Abstract
Recent genome-wide association studies (GWAS) of patient populations and genetic linkage assessments have demonstrated that the ankyrin-G (AnkG) gene is involved in neuropsychiatric disorders, including bipolar disorder, schizophrenia, and Alzheimer's disease, but it remains unclear how the genetic variants of AnkG contribute to neuropsychiatric disorders. Here, we generated AnkG hemizygous mice using the gene trapping approach. Homozygous AnkG was embryonically lethal. Western blotting and real-time polymerase chain reaction (qPCR) assessments of wild type (WT) and AnkG +/- mutant mice demonstrated a 50% reduction of ANKG levels, at the gene and protein levels, in AnkG hemizygous mice. In behavioral tests, AnkG hemizygous mice exhibited elevated anxiety- and depression-like traits, as well as cognitive impairment. Moreover, the expression levels of cognitive-related proteins (including metabotropic glutamate receptor subtype-1, brain-derived neurotrophic factor, postsynaptic density-95, GABA-B receptor, and GABA-A receptor alpha-1) were significantly decreased (P < 0.05), suggesting a possible role for AnkG in cognition. It is possible that the loss of AnkG in the brain disrupts the excitation/inhibition balance of neurotransmitters, hindering the synaptic plasticity of neurons, and consequently leading to abnormal behavioral symptoms. Therefore, AnkG possibly contributes to neuroprotection and normal brain function, and may constitute a new target for treating neuropsychiatric diseases, especially cognitive dysfunction.
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12
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Mitochondrial transcription factor A (TFAM) rs1937 and AP endonuclease 1 (APE1) rs1130409 alleles are associated with reduced cognitive performance. Neurosci Lett 2017; 645:46-52. [DOI: 10.1016/j.neulet.2017.02.062] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/15/2017] [Accepted: 02/22/2017] [Indexed: 12/13/2022]
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13
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Type 2 Diabetes, Obesity, and Risk for Dementia: Recent Insights into Brain Insulin Resistance and Hypometabolism. Curr Behav Neurosci Rep 2016. [DOI: 10.1007/s40473-016-0093-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
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14
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Gao L, Zhang Y, Deng J, Yu W, Yu Y. Polymorphisms of CHAT but not TFAM or VR22 are Associated with Alzheimer Disease Risk. Med Sci Monit 2016; 22:1924-35. [PMID: 27272392 PMCID: PMC4917321 DOI: 10.12659/msm.895984] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Background Alzheimer disease (AD) is a chronic neurodegenerative disease that is one of the most prevalent health problems among seniors. The cause of AD has not yet been elucidated, but many risk factors have been identified that might contribute to the pathogenesis and prognosis of AD. We conducted a meta-analysis of studies involving CHAT, TFAM, and VR22 polymorphisms and AD susceptibility to further understand the pathogenesis of AD. Material/Methods PubMed/Medline, Embase, Web of Science, the Cochrane Library, and Google Scholar were searched for relevant articles. Rs1880676, rs2177369, rs3810950, and rs868750 of CHAT; rs1937 and rs2306604 of TFAM; and rs10997691 and rs7070570 of VR22 are studied in this meta-analysis. Results A total of 51 case-control studies with 16 446 cases and 16 057 controls were enrolled. For CHAT, rs2177369 (G>A) in whites and rs3810950 (G>A) in Asians were found to be associated with AD susceptibility. No association was detected between rs1880676 and rs868750 and AD risk. For TFAM and VR22, no significant association was detected in studied single-nucleotide polymorphisms (SNPs). Conclusions Rs2177369 and rs3810950 of CHAT are associated with AD susceptibility, but rs1880676 and rs868750 are not. Rs1937 and rs2306604 of TFAM, and rs10997691 and rs7070570 of VR22 are not significantly associated with AD risk.
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Affiliation(s)
- Lili Gao
- Department of Neurology, The Affiliated Hiser Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Yan Zhang
- Department of Clinical Nutrition, The Affiliated Hiser Hospital of Qingdao University, Qingdao, Shandong, China (mainland)
| | - Jinghua Deng
- Department of Oral Mucosa, Stomatological Hospital, Yantai, Shandong, China (mainland)
| | - Wenbing Yu
- Fundamental Teaching Center, Ocean University of China, Qingdao, Shandong, China (mainland)
| | - Yunxia Yu
- Department of Neurology, People's Hospital of Haiyang City, Haiyang, Shandong, China (mainland)
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15
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Wang S, He F, Wang Y. Association between polymorphisms of the insulin-degrading enzyme gene and late-onset Alzheimer disease. J Geriatr Psychiatry Neurol 2015; 28:94-8. [PMID: 25414272 DOI: 10.1177/0891988714554707] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2013] [Accepted: 06/10/2014] [Indexed: 11/17/2022]
Abstract
The insulin-degrading enzyme (IDE) gene is a strong positional and biological candidate for late-onset Alzheimer disease (LOAD) susceptibility, with recent studies independently demonstrating an association between IDE gene variants and LOAD. However, previous data have been controversial. To investigate the relationship between IDE gene polymorphisms and LOAD risk, a case-control association study of 406 Han Chinese participants in Xinjiang, China, was undertaken. The LOAD and control groups consisted of 202 and 204 participants, respectively. The single-nucleotide polymorphisms rs1887922 and rs1999764 of the IDE gene were linked to LOAD incidence. The presence of the CT+CC genotype of rs1999764 had a protective effect compared to the TT genotype (adjusted P=.0001; odds ratio [OR]=0.226; 95% confidence interval [CI]=0.116-0.441), while the CT+CC genotype of rs1887922 was associated with increased LOAD risk (adjusted P=.0001; OR=3.640; 95% CI=1.889-7.016). Moreover, the effects of rs1887922 and rs1999764 were associated with LOAD risk independent of the apolipoprotein E ∊4 polymorphism and were more significant in men and women, respectively. These results demonstrate that the polymorphisms rs1887922 and rs1999764 of the IDE gene are associated with LOAD susceptibility in the Xinjiang Han population.
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Affiliation(s)
- Shitao Wang
- Department of Cardes Health Care, People's Hospital of Xinjiang Uygur Autonomous Region, Anhui Medical University, Urumqi, China
| | - Feiyan He
- Department of Cardes Health Care, People's Hospital of Xinjiang Uygur Autonomous Region, Anhui Medical University, Urumqi, China
| | - Ying Wang
- Department of Cardes Health Care, People's Hospital of Xinjiang Uygur Autonomous Region, Anhui Medical University, Urumqi, China
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Vite A, Li J, Radice GL. New functions for alpha-catenins in health and disease: from cancer to heart regeneration. Cell Tissue Res 2015; 360:773-83. [PMID: 25673211 DOI: 10.1007/s00441-015-2123-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 01/07/2015] [Indexed: 01/01/2023]
Abstract
Strong cell-cell adhesion mediated by adherens junctions is dependent on anchoring the transmembrane cadherin molecule to the underlying actin cytoskeleton. To do this, the cadherin cytoplasmic domain interacts with catenin proteins, which include α-catenin that binds directly to filamentous actin. Originally thought to be a static structure, the connection between the cadherin/catenin adhesion complex and the actin cytoskeleton is now considered to be dynamic and responsive to both intercellular and intracellular signals. Alpha-catenins are mechanosensing proteins that undergo conformational change in response to cytoskeletal tension thus modifying the linkage between the cadherin and the actin cytoskeleton. There are three α-catenin isoforms expressed in mouse and human: αE-catenin (CTNNA1), αN-catenin (CTNNA2) and αT-catenin (CTNNA3). This review summarizes recent progress in understanding the in vivo function(s) of α-catenins in tissue morphogenesis, homeostasis and disease. The role of α-catenin in the regulation of cellular proliferation will be discussed in the context of cancer and regeneration.
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Affiliation(s)
- Alexia Vite
- Department of Medicine, Center for Translational Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Suite 543E Jefferson Alumni Hall, 1020 Locust St., Philadelphia, PA, 19107, USA
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Abstract
In recent years good progress has been made in uncovering the genetic underpinnings of schizophrenia. Even so, as a polygenic disorder, schizophrenia has a complex etiology that is far from understood. Meanwhile data are being collected enabling the study of interactions between genes and the environment. A confluence of data from genetic and environmental exposure studies points to the role of infections and immunity in the pathophysiology of schizophrenia. In a recent study by Børglum et al., a single nucleotide polymorphism (SNP) in the gene CTNNA3 was identified that may provide clues to gene-environment interactions. The carriers of the minor allele for the SNP had a 5 fold risk of later developing schizophrenia if their mothers were CMV positive, while the children not carrying the allele had no excess risk from maternal CMV. In the current paper we summarize recent advances to clarify possible mechanism of such interactions between the host genotype and infection in schizophrenia risk.
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Affiliation(s)
- Jakob Grove
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
- iSEQ, Centre for Integrative Sequencing, Aarhus University, Denmark
| | - Anders D. Børglum
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
- iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Denmark
- iSEQ, Centre for Integrative Sequencing, Aarhus University, Denmark
- Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Denmark
| | - Brad D. Pearce
- Rollins School of Public Health, Department of Epidemiology, Emory University, Atlanta GA, USA
- Center for Translational Social Neuroscience, Emory University, Atlanta GA, USA
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Zhang H, Wang Y, Yan S, Du F, Wu L, Yan S, Yan SS. Genetic deficiency of neuronal RAGE protects against AGE-induced synaptic injury. Cell Death Dis 2014; 5:e1288. [PMID: 24922072 PMCID: PMC4611721 DOI: 10.1038/cddis.2014.248] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 04/28/2014] [Accepted: 05/05/2014] [Indexed: 01/11/2023]
Abstract
Synaptic dysfunction and degeneration is an early pathological feature of aging and age-related diseases, including Alzheimer's disease (AD). Aging is associated with increased generation and deposition of advanced glycation endproducts (AGEs), resulting from nonenzymatic glycation (or oxidation) proteins and lipids. AGE formation is accelerated in diabetes and AD-affected brain, contributing to cellular perturbation. The extent of AGEs' involvement, if at all, in alterations in synaptic structure and function is currently unknown. Here we analyze the contribution of neuronal receptor of AGEs (RAGE) signaling to AGE-mediated synaptic injury using novel transgenic neuronal RAGE knockout mice specifically targeted to the forebrain and transgenic mice expressing neuronal dominant-negative RAGE (DN-RAGE). Addition of AGEs to brain slices impaired hippocampal long-term potentiation (LTP). Similarly, treatment of hippocampal neurons with AGEs significantly decreases synaptic density. Such detrimental effects are largely reversed by genetic RAGE depletion. Notably, brain slices from mice with neuronal RAGE deficiency or DN-RAGE are resistant to AGE-induced LTP deficit. Further, RAGE deficiency or DN-RAGE blocks AGE-induced activation of p38 signaling. Taken together, these data show that neuronal RAGE functions as a signal transducer for AGE-induced synaptic dysfunction, thereby providing new insights into a mechanism by which the AGEs–RAGE-dependent signaling cascade contributes to synaptic injury via the p38 MAP kinase signal transduction pathway. Thus, RAGE blockade may be a target for development of interventions aimed at preventing the progression of cognitive decline in aging and age-related neurodegenerative diseases.
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Affiliation(s)
- Hongju Zhang
- 1] Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA [2] School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Yongfu Wang
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shijun Yan
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Fang Du
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Long Wu
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
| | - Shiqiang Yan
- School of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou, Gansu 730000, China
| | - Shirley S Yan
- Departments of Pharmacology and Toxicology and Higuchi Bioscience Center, School of Pharmacy, University of Kansas, Lawrence, KS 66047, USA
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Reitz C, Mayeux R. Genetics of Alzheimer's disease in Caribbean Hispanic and African American populations. Biol Psychiatry 2014; 75:534-41. [PMID: 23890735 PMCID: PMC3902050 DOI: 10.1016/j.biopsych.2013.06.003] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 06/06/2013] [Accepted: 06/07/2013] [Indexed: 01/16/2023]
Abstract
Late-onset Alzheimer's disease (LOAD), which is characterized by progressive deterioration in cognition, function, and behavior, is the most common cause of dementia and the sixth leading cause of all deaths, placing a considerable burden on Western societies. Most studies aiming to identify genetic susceptibility factors for LOAD have focused on non-Hispanic white populations. This is, in part related to differences in linkage disequilibrium and allele frequencies between ethnic groups that could lead to confounding. However, in addition, non-Hispanic white populations are simply more widely studied. As a consequence, minorities are genetically underrepresented despite the fact that in several minority populations living in the same community as whites (including African American and Caribbean Hispanics), LOAD incidence is higher. This review summarizes the current knowledge on genetic risk factors associated with LOAD risk in Caribbean Hispanics and African Americans and provides suggestions for future research. We focus on Caribbean Hispanics and African Americans because they have a high LOAD incidence and a body of genetic studies on LOAD that is based on samples with genome-wide association studies data and reasonably large effect sizes to yield generalizable results.
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Affiliation(s)
- Christiane Reitz
- Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY,Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY,Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY
| | - Richard Mayeux
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, New York; Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York; Gertrude H. Sergievsky Center, College of Physicians and Surgeons; Department of Epidemiology, Joseph P. Mailman School of Public Health, Columbia University, New York, New York; Department of Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York.
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Ye R, Carneiro AMD, Han Q, Airey D, Sanders-Bush E, Zhang B, Lu L, Williams R, Blakely RD. Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression. GENES BRAIN AND BEHAVIOR 2014; 13:261-75. [PMID: 24405699 DOI: 10.1111/gbb.12119] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 12/23/2013] [Accepted: 01/02/2014] [Indexed: 12/15/2022]
Abstract
Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) regulate 5-HT signaling via antidepressant-sensitive clearance of released neurotransmitter. Polymorphisms in the human SERT gene (SLC6A4) have been linked to risk for multiple neuropsychiatric disorders, including depression, obsessive-compulsive disorder and autism. Using BXD recombinant inbred mice, a genetic reference population that can support the discovery of novel determinants of complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic and molecular networks associated with SERT gene and protein expression. Correlational analyses revealed a network of genes that significantly associated with SERT mRNA levels. We quantified SERT protein expression levels and identified region- and gender-specific quantitative trait loci (QTLs), one of which associated with male midbrain SERT protein expression, centered on the protocadherin-15 gene (Pcdh15), overlapped with a QTL for midbrain 5-HT levels. Pcdh15 was also the only QTL-associated gene whose midbrain mRNA expression significantly associated with both SERT protein and 5-HT traits, suggesting an unrecognized role of the cell adhesion protein in the development or function of 5-HT neurons. To test this hypothesis, we assessed SERT protein and 5-HT traits in the Pcdh15 functional null line (Pcdh15(av-) (3J) ), studies that revealed a strong, negative influence of Pcdh15 on these phenotypes. Together, our findings illustrate the power of multidimensional profiling of recombinant inbred lines in the analysis of molecular networks that support synaptic signaling, and that, as in the case of Pcdh15, can reveal novel relationships that may underlie risk for mental illness.
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Affiliation(s)
- R Ye
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA
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Murdock DG, Bradford Y, Schnetz-Boutaud N, Mayo P, Allen MJ, D’Aoust LN, Liang X, Mitchell SL, Zuchner S, Small GW, Gilbert JR, Pericak-Vance MA, Haines JL. KIAA1462, a coronary artery disease associated gene, is a candidate gene for late onset Alzheimer disease in APOE carriers. PLoS One 2013; 8:e82194. [PMID: 24349219 PMCID: PMC3861372 DOI: 10.1371/journal.pone.0082194] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 10/22/2013] [Indexed: 11/19/2022] Open
Abstract
Alzheimer disease (AD) is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD). Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and "rokimi", encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either "rokimi", or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than "rokimi" which had no detectable expression in brain.
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Affiliation(s)
- Deborah G. Murdock
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Yuki Bradford
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Nathalie Schnetz-Boutaud
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Ping Mayo
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Melissa J. Allen
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Laura N. D’Aoust
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Xueying Liang
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Sabrina L. Mitchell
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
| | - Stephan Zuchner
- Miami Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Gary W. Small
- Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California, United States of America
| | - John R. Gilbert
- Miami Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Margaret A. Pericak-Vance
- Miami Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America
| | - Jonathan L. Haines
- Center for Human Genetics Research and Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, United States of America
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Ghani M, Sato C, Lee JH, Reitz C, Moreno D, Mayeux R, St George-Hyslop P, Rogaeva E. Evidence of recessive Alzheimer disease loci in a Caribbean Hispanic data set: genome-wide survey of runs of homozygosity. JAMA Neurol 2013; 70:1261-7. [PMID: 23978990 PMCID: PMC3991012 DOI: 10.1001/jamaneurol.2013.3545] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
IMPORTANCE The search for novel Alzheimer disease (AD) genes or pathologic mutations within known AD loci is ongoing. The development of array technologies has helped to identify rare recessive mutations among long runs of homozygosity (ROHs), in which both parental alleles are identical. Caribbean Hispanics are known to have an elevated risk for AD and tend to have large families with evidence of inbreeding. OBJECTIVE To test the hypothesis that the late-onset AD in a Caribbean Hispanic population might be explained in part by the homozygosity of unknown loci that could harbor recessive AD risk haplotypes or pathologic mutations. DESIGN We used genome-wide array data to identify ROHs (>1 megabase) and conducted global burden and locus-specific ROH analyses. SETTING A whole-genome case-control ROH study. PARTICIPANTS A Caribbean Hispanic data set of 547 unrelated cases (48.8% with familial AD) and 542 controls collected from a population known to have a 3-fold higher risk of AD vs non-Hispanics in the same community. Based on a Structure program analysis, our data set consisted of African Hispanic (207 cases and 192 controls) and European Hispanic (329 cases and 326 controls) participants. EXPOSURE Alzheimer disease risk genes. MAIN OUTCOMES AND MEASURES We calculated the total and mean lengths of the ROHs per sample. Global burden measurements among autosomal chromosomes were investigated in cases vs controls. Pools of overlapping ROH segments (consensus regions) were identified, and the case to control ratio was calculated for each consensus region. We formulated the tested hypothesis before data collection. RESULTS In total, we identified 17 137 autosomal regions with ROHs. The mean length of the ROH per person was significantly greater in cases vs controls (P = .0039), and this association was stronger with familial AD (P = .0005). Among the European Hispanics, a consensus region at the EXOC4 locus was significantly associated with AD even after correction for multiple testing (empirical P value 1 [EMP1], .0001; EMP2, .002; 21 AD cases vs 2 controls). Among the African Hispanic subset, the most significant but nominal association was observed for CTNNA3, a well-known AD gene candidate (EMP1, .002; 10 AD cases vs 0 controls). CONCLUSIONS AND RELEVANCE Our results show that ROHs could significantly contribute to the etiology of AD. Future studies would require the analysis of larger, relatively inbred data sets that might reveal novel recessive AD genes. The next step is to conduct sequencing of top significant loci in a subset of samples with overlapping ROHs.
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Affiliation(s)
- Mahdi Ghani
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Christine Sato
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Joseph H Lee
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York3Department of Epidemiolo
| | - Christiane Reitz
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Danielle Moreno
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Richard Mayeux
- Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center, Departments of Neurology, Psychiatry, and Medicine, College of Physicians and Surgeons, Columbia University, New York, New York
| | - Peter St George-Hyslop
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada4Department of Medicine, University of Toronto, Toronto, Ontario, Canada5Cambridge Institute for Medical Research and Department of Clinical Neuroscienc
| | - Ekaterina Rogaeva
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada4Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Neuronal apoptosis and motor deficits in mice with genetic inhibition of GSK-3 are Fas-dependent. PLoS One 2013; 8:e70952. [PMID: 23940673 PMCID: PMC3734180 DOI: 10.1371/journal.pone.0070952] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 06/24/2013] [Indexed: 11/19/2022] Open
Abstract
Glycogen synthase kinase-3 (GSK-3) inhibitors have been postulated as useful therapeutic tools for the treatment of chronic neurodegenerative and neuropsychiatric diseases. Nevertheless the clinical use of these inhibitors has been limited by their common side effects. Lithium, a non-selective GSK-3 inhibitor has been classically administered to treat bipolar patients but its prescription is decreasing due to its frequent side effects such as hand tremor. This toxicity seems to be higher in the elderly and a clinical trial with lithium for Alzheimer’s disease was stopped due to high rate of discontinuation. We have previously described a mechanism for the adverse effects of chronic lithium that involves neuronal apoptosis via Fas signaling. As lithium inhibits many other enzymatic activities such as inositol monophosphatase and histone deacetylase, here we aim to genetically test whether GSK-3 inhibition induces those adverse effects through Fas receptor. For this purpose we took advantage of a transgenic mouse line with decreased GSK-3 activity (Tet/DN-GSK-3 mice) that shows increased rate of neuronal apoptosis as well as motor deficits and brought it to a Fas deficient background (lpr mice). We found that apoptosis induced by GSK-3 inhibition was absent in Fas deficient background. Interestingly, motor deficits were also absent in Fas deficient Tet/DN-GSK-3 mice. These results demonstrate that Fas signaling contributes to the neurological toxicity of GSK-3 inhibition and suggest that a combination of GSK-3 inhibitors with blockers of Fas signaling could help to improve the application of GSK-3 inhibitors to clinics.
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Wu W, Jiang H, Wang M, Zhang D. Meta-analysis of the association between urokinase-plasminogen activator gene rs2227564 polymorphism and Alzheimer's disease. Am J Alzheimers Dis Other Demen 2013; 28:517-23. [PMID: 23813610 PMCID: PMC10852686 DOI: 10.1177/1533317513494450] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2024]
Abstract
OBJECTIVE The association between urokinase-plasminogen activator (PLAU) gene rs2227564 polymorphism and Alzheimer's disease (AD) risk has been widely reported across different ethnic populations, with inconsistent results. Thus, we performed a meta-analysis to assess the association between PLAU rs2227564 polymorphism and AD risk. METHODS Fixed or random effect model was used as the pooling method to assess the basis of homogeneity test among studies. Summarized estimation of odds ratio (OR) and 95% confidence interval (CI) were calculated. Heterogeneity among studies was evaluated using Q test and I (2). Publication bias was estimated using Harbord's test. RESULTS A total of 27 studies (comprising 6100 AD cases and 5718 controls) were included in this meta-analysis. The present meta-analysis showed a significant increased effect of T allele on risk of AD in dominant model (fixed effect model [FEM] OR 1.123, 95% CI 1.025-1.231) and heterozygote comparison (CT vs CC; FEM OR 1.126, 95% CI 1.027-1.235). No publication bias was detected. CONCLUSION This meta-analysis showed that T allele of rs2227564 polymorphism in PLAU gene could increase the effects on risk of AD, and this result needs to be confirmed by further studies.
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Affiliation(s)
- Wenlong Wu
- Department of Epidemiology and Health Statistics, Qingdao University Medical College, Qingdao, People’s Republic of China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines Physiology, Qingdao University medical college, Qingdao, People’s Republic of China
| | - Meiyun Wang
- Department of Epidemiology and Health Statistics, Qingdao University Medical College, Qingdao, People’s Republic of China
| | - Dongfeng Zhang
- Department of Epidemiology and Health Statistics, Qingdao University Medical College, Qingdao, People’s Republic of China
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LRRTM3 interacts with APP and BACE1 and has variants associating with late-onset Alzheimer's disease (LOAD). PLoS One 2013; 8:e64164. [PMID: 23750206 PMCID: PMC3672107 DOI: 10.1371/journal.pone.0064164] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2013] [Accepted: 04/09/2013] [Indexed: 01/11/2023] Open
Abstract
Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer’s disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ∼400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5′UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02–0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.
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Abstract
Serum antibodies against amyloid-β peptide (Aβ) in humans with or without diagnosis of Alzheimer's disease (AD) indicate the possibility of immune responses against brain antigens. In an unbiased screening for antibodies directed against brain proteins, we found in AD patients high serum levels of antibodies against the neuronal cytoskeletal protein ankyrin G (ankG); these correlated with slower rates of cognitive decline. Neuronal expression of ankG was higher in AD brains than in nondemented age-matched healthy control subjects. AnkG was present in exosomal vesicles, and it accumulated in β-amyloid plaques. Active immunization with ankG of arcAβ transgenic mice reduced brain β-amyloid pathology and increased brain levels of soluble Aβ(42). AnkG immunization induced a reduction in β-amyloid pathology, also in Swedish transgenic mice(.) Anti-ankG monoclonal antibodies reduced Aβ-induced loss of dendritic spines in hippocampal ArcAβ organotypic cultures. Together, these data established a role for ankG in the human adaptive immune response against resident brain proteins, and they show that ankG immunization reduces brain β-amyloid and its related neuropathology.
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Cui PJ, Cao L, Wang Y, Deng YL, Xu W, Wang G, Zhang Y, Zheng L, Fei QZ, Zhang T, Chen SD. The association between two single nucleotide polymorphisms within the insulin-degrading enzyme gene and Alzheimer's disease in a Chinese Han population. J Clin Neurosci 2013; 19:745-9. [PMID: 22502914 DOI: 10.1016/j.jocn.2011.08.036] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 07/08/2011] [Accepted: 08/15/2011] [Indexed: 11/29/2022]
Abstract
Several previous studies on the relationship between the insulin-degrading enzyme (IDE) gene and Alzheimer's disease (AD) have connected certain genetic variants to late-onset AD, in the absence of the apolipoprotein E (APOE)ε4 allele. However, the conclusions of these studies remain controversial. We investigated the association between two polymorphisms of IDE with AD in the Chinese population and found that the T/A genotype of rs4646958 had an important role in AD (adjusted p=0.007, odds ratio [OR]=2.796, 95% confidence interval [CI]=1.330-5.878), under the co-dominant genetic model. The T/C genotype of rs1887922 was also significantly associated with AD compared to the T/T genotype (adjusted p=0.003, OR=2.644, 95% CI=1.407-4.970). The C allele of rs1887922 conferred a higher risk of AD under the dominant genetics model (adjusted p=0.001, OR=2.719, 95% CI=1.472-5.022). Compared with the two other variant genotypes, the T/T genotype showed a protective effect in both polymorphisms (adjusted p=0.007, OR=0. 358, 95% CI=0.170-0.752 for rs4646958; adjusted p=0.001, OR=0. 368, 95% CI=0.199-0.679 in rs1887922). In the context of APOEε4-negative status, both variants were significantly associated with AD in some genetic models.
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Affiliation(s)
- Pei-Jing Cui
- Department of Neurology and Institute of Neurology, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, 197 2nd Rui Jin Road, Shanghai 200025, China
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Almeida A. Genetic determinants of neuronal vulnerability to apoptosis. Cell Mol Life Sci 2013; 70:71-88. [PMID: 22695677 PMCID: PMC11113535 DOI: 10.1007/s00018-012-1029-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Revised: 04/22/2012] [Accepted: 05/07/2012] [Indexed: 12/18/2022]
Abstract
Apoptosis is a common mode of cell death that contributes to neuronal loss associated with neurodegeneration. Single-nucleotide polymorphisms (SNPs) in chromosomal DNA are contributing factors dictating natural susceptibility of humans to disease. Here, the most common SNPs affecting neuronal vulnerability to apoptosis are reviewed in the context of neurological disorders. Polymorphic variants in genes encoding apoptotic proteins, either from the extrinsic (FAS, TNF-α, CASP8) or the intrinsic (BAX, BCL2, CASP3, CASP9) pathways could be highly valuable in the diagnosis of neurodegenerative diseases and stroke. Interestingly, the Arg72Pro SNP in TP53, the gene encoding tumor suppressor p53, was recently revealed a biomarker of poor prognosis in stroke due to its ability to modulate neuronal apoptotic death. Search for new SNPs responsible for genetic variability to apoptosis will ensure the implementation of novel diagnostic and prognostic tools, as well as therapeutic strategies against neurological diseases.
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Affiliation(s)
- Angeles Almeida
- Instituto de Investigación Biomédica de Salamanca, Hospital Universitario de Salamanca, 37007, Salamanca, Spain.
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Abstract
Alzheimer's disease (AD), the most common cause of dementia in aged populations, is believed to be caused by both environmental factors and genetic variations. Extensive linkage and association studies have established that a broad range of loci are associated with AD, including both causative and susceptibility (risk factor) genes. So far, at least three genes, APP, PS1, and PS2, have been identified as causative genes. Mutations in these genes have been found to cause mainly early-onset AD. On the other hand, APOE has been identified to be the most common high genetic risk factor for late-onset AD. Polymorphisms in the coding region, intron, and promoter region of certain genes constitute another kind of genetic variation associated with AD. A number of other genes or loci have been reported to have linkage with AD, but many show only a weak linkage or the results are not well reproduced. Currently, the measurable genetic associations account for about 50% of the population risk for AD. It is believed that more new loci will be found to associate with AD, either as causative genes or genetic risk factors, and that eventually the understanding of genetic factors in the pathogenesis of AD will be important for our efforts to cure this illness.
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Affiliation(s)
- Ya-Ping Tang
- Department of Psychiatry, The University of Chicago, 5841 S Maryland Avenue, Chicago, III, USA
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Choline acetyltransferase 2384G>a polymorphism and the risk of Alzheimer disease. Alzheimer Dis Assoc Disord 2012; 26:81-7. [PMID: 21602657 DOI: 10.1097/wad.0b013e31821cbcaf] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The potential association between choline acetyltransferase (CHAT) polymorphism and the risk of Alzheimer disease (AD) has been controversial. We examined the main effect of CHAT polymorphism and its interaction with apolipoprotein E (APOE) polymorphism in the development of AD in a well-powered elderly Korean sample. We analyzed CHAT 2384G>A polymorphism and APOE polymorphism among 736 Korean patients with probable AD and 1386 nondemented Korean controls. We tested the association between AD and CHAT genotype using a logistic regression model. In addition, we used generalized multifactor dimensionality reduction to investigate the interaction between CHAT and APOE with regard to the risk of AD. The CHAT A allele was associated with AD risk in a dose-dependent manner (odds ratio=1.40, 95% confidence interval=1.06-1.85, P=0.018 for heterozygotes; and odds ratio=3.92, 95% confidence interval=1.78-8.58, P=0.001 for homozygotes). The generalized multifactor dimensionality reduction approach identified a significant gene-gene interaction between CHAT and APOE (Balanced accuracy score=0.647, P=0.001). The CHAT A/A genotype was associated with earlier onset of AD (F=5.070, df=2, P=0.007). The CHAT A allele was associated with AD risk in a dose-dependent manner, and its interaction with the APOE ε4 allele was significant with regard to the development of AD. The CHAT A allele was also associated with earlier onset and possibly accelerated progression of AD.
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Synaptic dysfunction in Alzheimer's disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2012; 970:573-601. [PMID: 22351073 DOI: 10.1007/978-3-7091-0932-8_25] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Generation of amyloid peptide (Aβ) is at the beginning of a cascade that leads to Alzheimer's disease (AD). Amyloid precursor protein (APP), as well as β- and γ-secretases, is the principal player involved in Aβ production, while α-secretase cleavage on APP prevents Aβ deposition. Recent studies suggested that soluble assembly states of Aβ peptides can cause cognitive problems by disrupting synaptic function in the absence of significant neurodegeneration. Therefore, current research investigates the relative importance of these various soluble Aβ assemblies in causing synaptic dysfunction and cognitive deficits. Several Aβ oligomers targets and cellular mechanisms responsible of Aβ-induced synaptic failure have been identified. The first and most important mechanism impugns a toxic gain of function for Aβ which results due to self-association and attainment of new structures capable of novel interactions that lead to impaired plasticity. Other scenarios predicate that Aβ has a normal physiological role. On the one hand, insufficient Aβ could lead to a loss of normal function, whereas excess Aβ may precipitate dysfunction. How this occurs and which the main target/s is/are for the synaptic action of Aβ remains to be fully understood and would certainly represent one of the main challenges to future AD research.
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Abstract
AbstractPTEN (phosphatase and tensin homologue deleted in chromosome 10) was first identified as a candidate tumour suppressor gene located on chromosome 10q23. It is considered as one of the most frequently mutated genes in human malignancies. Emerging evidence shows that the biological function of PTEN extends beyond its tumour suppressor activity. In the central nervous system PTEN is a crucial regulator of neuronal development, neuronal survival, axonal regeneration and synaptic plasticity. Furthermore, PTEN has been linked to the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Recently increased attention has been focused on PTEN as a potential target for the treatment of brain injury and neurodegeneration. In this review we discuss the essential functions of PTEN in the central nervous system and its involvement in neurodegeneration.
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Farrer L, Logue M. Collection of clinical and epidemiological data for genetic linkage and association studies. CURRENT PROTOCOLS IN HUMAN GENETICS 2012; Chapter 1:Unit1.1. [PMID: 22241654 DOI: 10.1002/0471142905.hg0101s72] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Modern gene-mapping can include linkage studies, which correlate the presence of disease to broad genomic regions in either small or large family units, and association studies, which can narrow the location of a disease-predisposing trait to a single gene using either case-control or family data. This unit provides an overview of key concepts and presents guidelines for collecting diagnostic, epidemiological, and genealogical data from potential study participants. The commentary discusses the use of publicly available data from online resources, methods for evaluating evidence of genetic versus environmental influences in a disease or disease-related endophenotype, and use of e-forms to capture data electronically.
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Affiliation(s)
- Lindsay Farrer
- Boston University School of Medicine, Boston, Massachusetts, USA
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Choi Y, Marchani EE, Bird TD, Steinbart EJ, Blacker D, Wijsman EM. Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:785-98. [PMID: 21812099 PMCID: PMC3168696 DOI: 10.1002/ajmg.b.31220] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2011] [Accepted: 07/06/2011] [Indexed: 01/01/2023]
Abstract
Alzheimer's disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early onset AD, only the APOE gene is known to have a high contribution to risk of the common late-onset form of the disease (LOAD, onset >60 years). APOE genotypes vary in their AD risk as well as age-at-onset distributions, and it is likely that other loci will similarly affect AD age-at-onset. Here we present the first analysis of age-at-onset in the NIMH LOAD sample that allows for both a multilocus trait model and genetic heterogeneity among the contributing sites, while at the same time accommodating age censoring, effects of known genetic covariates, and full pedigree and marker information. The results provide evidence for genomic regions not previously implicated in this data set, including regions on chromosomes 7q, 15, and 19p. They also affirm evidence for loci on chromosomes 1q, 6p, 9q, 11, and, of course, the APOE locus on 19q, all of which have been reported previously in the same sample. The analyses failed to find evidence for linkage to chromosome 10 with inclusion of unaffected subjects and extended pedigrees. Several regions implicated in these analyses in the NIMH sample have been previously reported in genome scans of other AD samples. These results, therefore, provide independent confirmation of AD loci in family-based samples on chromosomes 1q, 7q, 19p, and suggest that further efforts towards identifying the underlying causal loci are warranted.
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Affiliation(s)
- Yoonha Choi
- Department of Biostatistics, University of Washington, Seattle, WA
| | - Elizabeth E. Marchani
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA
| | - Thomas D. Bird
- Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA,Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA,Department of Neurology, University of Washington, Seattle, WA
| | - Ellen J. Steinbart
- Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System, Seattle Division, Seattle, WA,Department of Neurology, University of Washington, Seattle, WA
| | - Deborah Blacker
- Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School; Dept of Epidemiology, Harvard School of Public Health; Boston, MA
| | - Ellen M. Wijsman
- Department of Biostatistics, University of Washington, Seattle, WA,Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA,Department of Genome Sciences, University of Washington, Seattle, WA,correspondence to Ellen M. Wijsman, Department of Medicine, Division of Medical Genetics, Box 357720, University of Washington, Seattle, WA 98195-7720. (206) 543-8987.
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Bartl J, Scholz CJ, Hinterberger M, Jungwirth S, Wichart I, Rainer MK, Kneitz S, Danielczyk W, Tragl KH, Fischer P, Riederer P, Grünblatt E. Disorder-specific effects of polymorphisms at opposing ends of the Insulin Degrading Enzyme gene. BMC MEDICAL GENETICS 2011; 12:151. [PMID: 22107728 PMCID: PMC3266204 DOI: 10.1186/1471-2350-12-151] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2011] [Accepted: 11/22/2011] [Indexed: 01/05/2023]
Abstract
Background Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aβ) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. Methods We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aβ42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. Results The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aβ42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. Conclusions Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.
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Affiliation(s)
- Jasmin Bartl
- Department of Psychiatry, Psychosomatic and Psychotherapy, University Hospital of Wuerzburg, Fuechsleinstr, 15, D-97080 Wuerzburg, Germany.
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Friedrich P, Feulner T, Laws S, Eckart K, Perneczky R, Kurz A, Förstl H, Riemenschneider M. No association of Tachykinin receptor 2 (TACR2) polymorphisms with Alzheimer's disease. Neurobiol Aging 2011; 32:544-5. [DOI: 10.1016/j.neurobiolaging.2009.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2008] [Revised: 02/16/2009] [Accepted: 03/14/2009] [Indexed: 10/20/2022]
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Mitochondrial transcription factor A (TFAM) polymorphisms and risk of late-onset Alzheimer's disease in Han Chinese. Brain Res 2011; 1368:355-60. [DOI: 10.1016/j.brainres.2010.10.074] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 10/18/2010] [Accepted: 10/18/2010] [Indexed: 12/17/2022]
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Sherva R, Baldwin CT, Inzelberg R, Vardarajan B, Cupples LA, Lunetta K, Bowirrat A, Naj A, Pericak-Vance M, Friedland RP, Farrer LA. Identification of novel candidate genes for Alzheimer's disease by autozygosity mapping using genome wide SNP data. J Alzheimers Dis 2011; 23:349-59. [PMID: 21098978 PMCID: PMC3819807 DOI: 10.3233/jad-2010-100714] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Alzheimer's disease (AD) is highly prevalent in Wadi Ara despite the low frequency of apolipoprotein E ε4 in this genetically isolated Arab community in northern Israel. We hypothesized that the reduced genetic variability in combination with increased homozygosity would facilitate identification of genetic variants that contribute to the high rate of AD in this community. AD cases (n = 124) and controls (n = 142) from Wadi Ara were genotyped for a genome-wide set of more than 300,000 single nucleotides polymorphisms (SNPs) which were used to calculate measures of population stratification and inbreeding, and to identify regions of autozygosity. Although a high degree of relatedness was evident in both AD cases and controls, controls were significantly more related and contained more autozygous regions than AD cases (p = 0.004). Eight autozygous regions on seven different chromosomes were more frequent in controls than the AD cases, and 116 SNPs in these regions, primarily on chromosomes 2, 6, and 9, were nominally associated with AD. The association with rs3130283 in AGPAT1 on chromosome 6 was observed in a meta-analysis of seven genome-wide association study (GWAS) datasets. Analysis of the full Wadi Ara GWAS dataset revealed 220 SNP associations with AD at p ≤ 10⁻⁵, and seven of these were confirmed in the replication GWAS datasets (p < 0.05). The unique population structure of Wadi Ara enhanced efforts to identify genetic variants that might partially explain the high prevalence of AD in the region. Several of these variants show modest evidence for association in other Caucasian populations.
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Affiliation(s)
- Richard Sherva
- Department of Medicine (Genetics Program), Boston University School of Medicine, Boston, MA, USA
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Wang F, Shu C, Jia L, Zuo X, Zhang Y, Zhou A, Qin W, Song H, Wei C, Zhang F, Hong Z, Tang M, Wang DM, Jia J. Exploration of 16 candidate genes identifies the association of IDE with Alzheimer's disease in Han Chinese. Neurobiol Aging 2010; 33:1014.e1-9. [PMID: 20880607 DOI: 10.1016/j.neurobiolaging.2010.08.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2010] [Revised: 07/20/2010] [Accepted: 08/09/2010] [Indexed: 01/16/2023]
Abstract
Alzheimer's disease (AD) has a complex pattern of inheritance and many genes have recently been reported to contribute to the disease susceptibility. We selected 106 SNPs within 16 candidate genes and performed a multistage association study using 4 sample sets consisting of 731 AD patients and 738 control subjects to identify genetic factors for AD in Han Chinese. A single nucleotide polymorphism (SNP) in the insulin degrading enzyme gene (IDE), rs3781239, showed a significant association with AD. The C allele increased the risk of AD 1.72-fold than the G allele (odds ratio [OR] = 1.72, 95% confidence interval [CI] = 1.17-2.53, p = 0.006) and CC carriers had a 4.89-fold higher risk for AD than that of the carriers with CG and GG genotypes (odds ratio = 4.89, 95% CI = 1.85-12.91, p = 0.001). Moreover, the CC genotype was significantly associated with earlier age at onset (p = 0.001, hazard ratio [HR] = 2.09, 95% CI = 1.38-3.18). Our data suggest that the polymorphism of IDE is associated with susceptibility to Alzheimer's disease in Han Chinese.
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Affiliation(s)
- Fen Wang
- Department of Neurology, Xuan Wu Hospital of the Capital Medical University, Beijing, China
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Abstract
With the advent of technologies that allow simultaneous genotyping of thousands of single-nucleotide polymorphisms (SNPs) across the genome, the genetic contributions to complex diseases can be explored at an unprecedented detail. This study is among the first to apply the genome-wide association study (GWAS) approach to Alzheimer disease (AD). We present our GWAS results from the German population for genes included in the 'Top Results' list on the AlzGene database website. In addition to the apolipoprotein E locus, we identified nominally significant association signals in six of the ten genes investigated, albeit predominantly for SNPs other than those already published as being disease associated. Further, all of the four AD genes previously identified through GWAS also showed nominally significant association signals in our data. The results of our comparative study reinforce the necessity for replication and validation, not only of GWAS but also of candidate gene case-control studies, in different populations. Furthermore, cross-platform comparison of genotyping results can also identify new association signals. Finally, our data confirm that GWAS, regardless of the platform, are valuable for the identification of genetic variants associated with AD.
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Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV, Carassquillo MM, Lambert JC, Harold D, Schrijvers EMC, Ramirez-Lorca R, Debette S, Longstreth WT, Janssens ACJW, Pankratz VS, Dartigues JF, Hollingworth P, Aspelund T, Hernandez I, Beiser A, Kuller LH, Koudstaal PJ, Dickson DW, Tzourio C, Abraham R, Antunez C, Du Y, Rotter JI, Aulchenko YS, Harris TB, Petersen RC, Berr C, Owen MJ, Lopez-Arrieta J, Varadarajan BN, Becker JT, Rivadeneira F, Nalls MA, Graff-Radford NR, Campion D, Auerbach S, Rice K, Hofman A, Jonsson PV, Schmidt H, Lathrop M, Mosley TH, Au R, Psaty BM, Uitterlinden AG, Farrer LA, Lumley T, Ruiz A, Williams J, Amouyel P, Younkin SG, Wolf PA, Launer LJ, Lopez OL, van Duijn CM, Breteler MMB. Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 2010; 303:1832-40. [PMID: 20460622 PMCID: PMC2989531 DOI: 10.1001/jama.2010.574] [Citation(s) in RCA: 972] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
CONTEXT Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE Presence of Alzheimer disease. RESULTS Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.
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Affiliation(s)
- Sudha Seshadri
- Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA
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George AJ, Gordon L, Beissbarth T, Koukoulas I, Holsinger RMD, Perreau V, Cappai R, Tan SS, Masters CL, Scott HS, Li QX. A serial analysis of gene expression profile of the Alzheimer's disease Tg2576 mouse model. Neurotox Res 2010; 17:360-79. [PMID: 19760337 DOI: 10.1007/s12640-009-9112-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2009] [Revised: 06/22/2009] [Accepted: 08/31/2009] [Indexed: 10/20/2022]
Abstract
Serial analysis of gene expression (SAGE), a technique that allows for the simultaneous detection of expression levels of the entire genome without a priori knowledge of gene sequences, was used to examine the transcriptional expression pattern of the Tg2576 mouse model of Alzheimer's disease (AD). Pairwise comparison between the Tg2576 and nontransgenic SAGE libraries identified a number of differentially expressed genes in the Tg2576 SAGE library, some of which were not previously revealed by the microarray studies. Real-time PCR was used to validate a panel of genes selected from the SAGE analysis in the Tg2576 mouse brain, as well as the hippocampus and temporal cortex of sporadic AD and normal age-matched controls. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 5 (NDUFA5) and FXYD domain-containing ion transport regulator 6 (FXYD6) were found to be significantly decreased in the Tg2576 mouse brain and AD hippocampus. PTEN-induced putative kinase 1 (PINK1), phosphatidylethanolamine binding protein (PEBP), crystalline mu (CRYM), and neurogranin (NRGN) were significantly decreased in AD tissues. The gene ontologies represented in the Tg2576 data were statistically analyzed and demonstrated a significant under-representation of genes involved with G-protein-coupled receptor signaling and odorant binding, while genes significantly over-represented were focused on cellular communication and cellular physiological processes. The novel approach of profiling the Tg2576 mouse brain using SAGE has identified different genes that could subsequently be examined for their potential as peripheral diagnostic and prognostic markers for Alzheimer's disease.
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Affiliation(s)
- Amee J George
- Department of Pathology, The University of Melbourne and The Mental Health Research Institute of Victoria, Parkville, VIC 3052, Australia
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Zou F, Carrasquillo MM, Pankratz VS, Belbin O, Morgan K, Allen M, Wilcox SL, Ma L, Walker LP, Kouri N, Burgess JD, Younkin LH, Younkin SG, Younkin CS, Bisceglio GD, Crook JE, Dickson DW, Petersen RC, Graff-Radford N, Younkin SG, Ertekin-Taner N. Gene expression levels as endophenotypes in genome-wide association studies of Alzheimer disease. Neurology 2010; 74:480-6. [PMID: 20142614 DOI: 10.1212/wnl.0b013e3181d07654] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Late-onset Alzheimer disease (LOAD) is a common disorder with a substantial genetic component. We postulate that many disease susceptibility variants act by altering gene expression levels. METHODS We measured messenger RNA (mRNA) expression levels of 12 LOAD candidate genes in the cerebella of 200 subjects with LOAD. Using the genotypes from our LOAD genome-wide association study for the cis-single nucleotide polymorphisms (SNPs) (n = 619) of these 12 LOAD candidate genes, we tested for associations with expression levels as endophenotypes. The strongest expression cis-SNP was tested for AD association in 7 independent case-control series (2,280 AD and 2,396 controls). RESULTS We identified 3 SNPs that associated significantly with IDE (insulin degrading enzyme) expression levels. A single copy of the minor allele for each significant SNP was associated with approximately twofold higher IDE expression levels. The most significant SNP, rs7910977, is 4.2 kb beyond the 3' end of IDE. The association observed with this SNP was significant even at the genome-wide level (p = 2.7 x 10(-8)). Furthermore, the minor allele of rs7910977 associated significantly (p = 0.0046) with reduced LOAD risk (OR = 0.81 with a 95% CI of 0.70-0.94), as expected biologically from its association with elevated IDE expression. CONCLUSIONS These results provide strong evidence that IDE is a late-onset Alzheimer disease (LOAD) gene with variants that modify risk of LOAD by influencing IDE expression. They also suggest that the use of expression levels as endophenotypes in genome-wide association studies may provide a powerful approach for the identification of disease susceptibility alleles.
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Affiliation(s)
- F Zou
- Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA
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Fallin MD, Szymanski M, Wang R, Gherman A, Bassett SS, Avramopoulos D. Fine mapping of the chromosome 10q11-q21 linkage region in Alzheimer's disease cases and controls. Neurogenetics 2010; 11:335-48. [PMID: 20182759 DOI: 10.1007/s10048-010-0234-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Accepted: 01/15/2010] [Indexed: 10/19/2022]
Abstract
We have previously reported strong linkage on chromosome 10q in pedigrees transmitting Alzheimer's disease through the mother, overlapping with many significant linkage reports including the largest reported study. Here, we report the most comprehensive fine mapping of this region to date. In a sample of 638 late-onset Alzheimer's disease (LOAD) cases and controls including 104 maternal LOAD cases, we genotyped 3,884 single nucleotide polymorphisms (SNPs) covering 15.2 Mb. We then used imputations and publicly available data to generate an extended dataset including 4,329 SNPs for 1,209 AD cases and 839 controls in the same region. Further, we screened eight genes in this region for rare alleles in 283 individuals by nucleotide sequencing, and we tested for possible monoallelic expression as it might underlie our maternal parent of origin linkage. We excluded the possibility of multiple rare coding risk variants for these genes and monoallelic expression when we could test for it. One SNP, rs10824310 in the PRKG1 gene, showed study-wide significant association without a parent of origin effect, but the effect size estimate is not of sufficient magnitude to explain the linkage, and no association is observed in an independent genome-wide association studies (GWAS) report. Further, no causative variants were identified though sequencing. Analysis of cases with maternal disease origin pointed to a few regions of interest that included the genes PRKG1 and PCDH15 and an intergenic interval of 200 Kb. It is likely that non-transcribed rare variants or other mechanisms involving these genomic regions underlie the observed linkage and parent of origin effect. Acquiring additional support and clarifying the mechanisms of such involvement is important for AD and other complex disorder genetics research.
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Affiliation(s)
- Margaret Daniele Fallin
- Department of Epidemiology, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA
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Alper BJ, Rowse JW, Schmidt WK. Yeast Ste23p shares functional similarities with mammalian insulin-degrading enzymes. Yeast 2010; 26:595-610. [PMID: 19750477 DOI: 10.1002/yea.1709] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
The S. cerevisiae genome encodes two M16A enzymes: Axl1p and Ste23p. Of the two, Ste23p shares significantly higher sequence identity with M16A enzymes from other species, including mammalian insulin-degrading enzymes (IDEs). In this study, recombinant Ste23p and R. norvegicus IDE (RnIDE) were isolated from E. coli, and their enzymatic properties compared. Ste23p was found to cleave established RnIDE substrates, including the amyloid-beta peptide (Abeta1-40) and insulin B-chain. A novel internally quenched fluorogenic substrate (Abz-SEKKDNYIIKGV-nitroY-OH) based on the polypeptide sequence of the yeast P2 a-factor mating propheromone was determined to be a suitable substrate for both Ste23p and RnIDE, and was used to conduct comparative enzymological studies. Both enzymes were most active at 37 degrees C, in alkaline buffers and in high salt environments. In addition, the proteolytic activities of both enzymes towards the fluorogenic substrate were inhibited by metal chelators, thiol modifiers, inhibitors of cysteine protease activity and insulin. Characteristics of STE23 expression were also evaluated. Our analysis indicates that the 5' terminus of the STE23 gene has been mischaracterized, with the physiologically relevant initiator corresponding to residue M53 of the publicly annotated protein sequence. Finally, we demonstrate that, unlike haploid-specific Axl1p, Ste23p is expressed in both haploid and diploid cell types. Our study presents the first comprehensive biochemical analysis of a yeast M16A enzyme, and provides evidence that S. cerevisiae Ste23p has enzymatic properties that are highly consistent with mammalian IDEs and other M16A enzymes.
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Affiliation(s)
- Benjamin J Alper
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
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The FAS gene, brain volume, and disease progression in Alzheimer's disease. Alzheimers Dement 2009; 6:118-24. [PMID: 19766542 DOI: 10.1016/j.jalz.2009.05.663] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2009] [Revised: 05/04/2009] [Accepted: 05/04/2009] [Indexed: 11/23/2022]
Abstract
OBJECTIVE We sought to identify single-nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) progression and brain volume. METHODS Ninety-seven SNPs were genotyped in 243 subjects from a longitudinal study of healthy aging. Subjects who received a diagnosis of cognitive impairment (CI) at any study visit (before their most recent visit) and had DNA in the study's DNA bank were included. Progression of AD was defined as the duration from onset of CI to diagnosis of AD. Association of each of the 97 SNPs with AD progression was tested via Cox model. Those SNPs meeting a criterion of nominal significance (P < 0.05) for association with AD progression were reassessed to account for multiple testing by repeating the marker selection process in 10,000 random permutations. Next, the association between the one SNP that survived the multiple-testing adjustment and brain volume was determined by multiple regression analysis in a subgroup of subjects for whom magnetic-resonance imaging (MRI)-derived brain-volume data were available. Brain volumes were adjusted for age at MRI, gender, and time from MRI to onset of CI. RESULTS The minor allele of rs1468063 in the FAS gene, which is member 6 of the tumor necrosis factor receptor superfamily, was significantly associated with faster AD progression after adjustment for multiple testing (P(permutation) = 0.049). The same allele in rs1468063 was associated with smaller brain volumes and larger ventricular volumes (P = 0.02 and 0.04, respectively). CONCLUSIONS The FAS gene, which plays a role in apoptosis, may be associated with AD by modulating the apoptosis and neuronal loss secondary to AD neuropathology.
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Lloyd SE, Rossor M, Fox N, Mead S, Collinge J. HECTD2, a candidate susceptibility gene for Alzheimer's disease on 10q. BMC MEDICAL GENETICS 2009; 10:90. [PMID: 19754925 PMCID: PMC2753310 DOI: 10.1186/1471-2350-10-90] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/02/2009] [Accepted: 09/15/2009] [Indexed: 12/31/2022]
Abstract
Background Late onset Alzheimer's disease (LOAD) is a neurodegenerative disorder characterised by the deposition of amyloid plaques and neurofibrillary tangles in the brain and is the major cause of dementia. Multiple genetic loci, including 10q, have been implicated in LOAD but to date, with the exception of APOE, the underlying genes have not been identified. HECTD2 maps to 10q and has been implicated in susceptibility to human prion diseases which are also neurodegenerative conditions associated with accumulation of misfolded host proteins. In this study we test whether the HECTD2 susceptibility allele seen in prion disease is also implicated in LOAD. Methods DNA from 320 individuals with Alzheimer's disease and 601 controls were genotyped for a HECTD2 intronic tagging SNP, rs12249854 (A/T). Groups were further analysed following stratification by APOE genotype. Results The rs12249854 minor allele (A) frequency was higher (5.8%) in the Alzheimer's disease group as compared to the controls (3.9%), however, this was not statistically significant (P = 0.0668). No significant difference was seen in minor allele frequency in the presence or absence of the APOE ε4 allele. Conclusion The common haplotypes of HECTD2, tagged by rs12249854, are not associated with susceptibility to LOAD.
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Affiliation(s)
- Sarah E Lloyd
- MRC Prion Unit, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK.
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Behl M, Zhang Y, Zheng W. Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure. Cerebrospinal Fluid Res 2009; 6:11. [PMID: 19747378 PMCID: PMC2753621 DOI: 10.1186/1743-8454-6-11] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2009] [Accepted: 09/11/2009] [Indexed: 11/28/2022] Open
Abstract
Background Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (Aβ) peptides in the brain extracellular matrix, resulting in pathological changes and neurobehavioral deficits. Previous work from this laboratory demonstrated that the choroid plexus (CP) possesses the capacity to remove Aβ from the cerebrospinal fluid (CSF), and exposure to lead (Pb) compromises this function. Since metalloendopeptidase insulin-degrading enzyme (IDE), has been implicated in the metabolism of Aβ, we sought to investigate whether accumulation of Aβ following Pb exposure was due to the effect of Pb on IDE. Methods Rats were injected with a single dose of Pb acetate or an equivalent concentration of Na-acetate; CP tissues were processed to detect the location of IDE by immunohistochemistry. For in vitro studies, choroidal epithelial Z310 cells were treated with Pb for 24 h in the presence or absence of a known IDE inhibitor, N-ethylmaleimide (NEM) to assess IDE enzymatic activity and subsequent metabolic clearance of Aβ. Additionally, the expression of IDE mRNA and protein were determined using real time PCR and western blots respectively. Results Immunohistochemistry and confocal imaging revealed the presence of IDE towards the apical surface of the CP tissue with no visible alteration in either its intensity or location following Pb exposure. There was no significant difference in the expressions of either IDE mRNA or protein following Pb exposure compared to controls either in CP tissues or in Z310 cells. However, our findings revealed a significant decrease in the IDE activity following Pb exposure; this inhibition was similar to that seen in the cells treated with NEM alone. Interestingly, treatment with Pb or NEM alone significantly increased the levels of intracellular Aβ, and a greater accumulation of Aβ was seen when the cells were exposed to a combination of both. Conclusion These data suggest that Pb exposure inhibits IDE activity but does not affect its expression in the CP. This, in turn, leads to a disrupted metabolism of Aβ resulting in its accumulation at the blood-CSF barrier.
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Affiliation(s)
- Mamta Behl
- School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA.
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Lefebvre T, Dehennaut V, Guinez C, Olivier S, Drougat L, Mir AM, Mortuaire M, Vercoutter-Edouart AS, Michalski JC. Dysregulation of the nutrient/stress sensor O-GlcNAcylation is involved in the etiology of cardiovascular disorders, type-2 diabetes and Alzheimer's disease. Biochim Biophys Acta Gen Subj 2009; 1800:67-79. [PMID: 19732809 DOI: 10.1016/j.bbagen.2009.08.008] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2009] [Revised: 08/17/2009] [Accepted: 08/24/2009] [Indexed: 11/19/2022]
Abstract
O-GlcNAcylation is widespread within the cytosolic and nuclear compartments of cells. This post-translational modification is likely an indicator of good health since its intracellular level correlates with the availability of extracellular glucose. Apart from its status as a nutrient sensor, O-GlcNAcylation may also act as a stress sensor since it exerts its fundamental effects in response to stress. Several studies report that the cell quickly responds to an insult by elevating O-GlcNAcylation levels and by unmasking a newly described Hsp70-GlcNAc binding property. From a more practical point of view, it has been shown that O-GlcNAcylation impairments contribute to the etiology of cardiovascular diseases, type-2 diabetes and Alzheimer's disease (AD), three illnesses common in occidental societies. Many studies have demonstrated that O-GlcNAcylation operates as a powerful cardioprotector and that by raising O-GlcNAcylation levels, the organism more successfully resists trauma-hemorrhage and ischemia/reperfusion injury. Recent data have also shown that insulin resistance and, more broadly, type-2 diabetes can be controlled by O-GlcNAcylation of the insulin pathway and O-GlcNAcylation of the gluconeogenesis transcription factors FoxO1 and CRCT2. Lastly, the finding that AD may correspond to a type-3 diabetes offers new perspectives into the knowledge of the neuropathology and into the search for new therapeutic avenues.
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Affiliation(s)
- Tony Lefebvre
- CNRS-UMR 8576, Unit of Structural and Functional Glycobiology, IFR 147, University of Lille 1, Villeneuve d'Ascq, France.
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Lambert JC, Campagne F, Marambaud P. [CALHM1, a novel gene to blame in Alzheimer disease]. Med Sci (Paris) 2009; 24:923-4. [PMID: 19038093 DOI: 10.1051/medsci/20082411923] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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