Trehalose has been proposed as a possible therapeutic option for attenuating the neuropathological changes associated with neurodegeneration, including Alzheimer's disease (AD). The administration of trehalose in human and murine models was linked to restoring antioxidant status, decreasing lipoperoxidation, and alleviating neuroinflammation. This latter biochemical mechanism was associated with the upregulation of specific brain-enriched microRNAs (miRNA). Herein, using a direct hybridization approach, we evaluate trehalose intravenous treatment in AD patients, conducting a phase two clinical trial (IRCT20130829014521N15) examining the alteration of microRNA profiles before and after the treatment. Twenty patients were recruited and randomly assigned to two groups: the intervention group received 15 g/week of intravenous trehalose. The control group received placebo in the form of normal saline. The period chosen was 12 weeks. Blood samples were obtained at the beginning and end of the study. Circulating microRNAs expression data between the placebo and treatment groups were assessed using microarray analysis. Subsequently, differentially expressed (DE) miRNAs specific to the trehalose-treated group were identified, and their gene targets were determined by bioinformatics-based approaches. The analysis of DE miRNAs pointed out modulation in unique miRNAs between treatment and placebo groups. Specifically, hsa-miR-1268a, -3605-3p, -555, and -6511a-3p were significantly downregulated, while hsa-miR-324-3p and -539-5p showed significant upregulation. Of the 147 overlapped validated genes identified in the bioinformatics analysis, several are related to autophagy, protein aggregation, oxidative stress, and inflammation. KEGG enrichment pathways reveal regulation of actin cytoskeleton, axon guidance, and neurotrophin signaling pathways. The results identify significant modulation in unique miRNAs in AD patients under trehalose. These findings suggest the potential utility of these microRNAs as biomarkers for trehalose pharmacological monitoring in AD.

RLIP76 (Rlip), a stress-responsive protein, plays a multifaceted role in cellular function. This protein acts primarily as a glutathione-electrophile conjugate (GS-E) transporter, crucial for detoxifying hazardous compounds and converting them into mercapturic acids. RLIP76 also modulates cytoskeletal motility and membrane plasticity through its role in the Ral-signaling pathway, interacting with RalA and RalB, key small GTPases involved in growth and metastasis. Beyond its ATP-dependent transport functions in various tissues, RLIP76 also demonstrates GTPase Activating Protein (GAP) activity towards Rac1 and Cdc42, with a preference for Ral-GTP over Ral-GDP. Its functions span critical physiological processes including membrane dynamics, oxidative stress response, and mitochondrial dynamics. The protein's widespread expression and evolutionary conservation underscore its significance. Our lab discovered that Rlip interacts with Alzheimer's disease (AD) proteins, amyloid beta and phosphorylated and induce oxidative stress, mitochondrial dysfnction and synaptic damage in AD. Our in vitro studies revealed that overexpression of Rlip reduces mitochondrial abnormalities. Further, our in vivo studies (Rlip+/- mice) revealed that a partial reduction of Rlip in mice (Rlip+/-), leads to mitochondrial abnormalities, elevated oxidative stress, and cognitive deficits resembling late-onset AD, emphasizing the protein's crucial role in neuronal health and disease. Finally, we discuss the experimental cross-breedings of overexpression of mice Rlip TG/TG or Rlip + /- mice with Alzheimer's disease models - earlyonset 5XFAD, late-onset APPKI and Tau transgenic mice, providing new insights into RLIP76's role in AD progression and development. This review summarizes RLIP76's structure, function, and cellular pathways, highlighting its implications in AD and its potential as a therapeutic target.

Although the pathogenesis of Alzheimer's disease (AD) is still unknown, the molecular pathological phenomena is clear, mainly due to mitochondrial dysfunction and central nervous system inflammation caused by imbalanced antioxidant capacity and synaptic dysfunction, so antioxidant therapy is still the preferred treatment for AD. However, although antioxidant enzymes have high catalytic efficiency, the substrate spectrum is narrow; Antioxidants have wider range of effects, but their efficiency is low. Since the antioxidant defense system in high-grade organisms is composed of both enzymatic and non-enzymatic systems, therefore we synthesized a metal-organic framework (MOF) with superoxide dismutase activity, and depending on the interface potential effect, curcumin was loaded to construct a synergistic antioxidant treatment system. More importantly, due to the complementary surface electrostatic potential between MOF and curcumin, the system exhibited both good antioxidant activity and efficient β-amyloid plaque scavenging ability, which slowed down the cognitive dysfunction in the brain of AD mice.

Apoptosis can be known as a key factor in the pathogenesis of neurodegenerative disorders. In disease conditions, the rate of apoptosis expands and tissue damage may become apparent. Recently, the scientific studies of the non-coding RNAs (ncRNAs) has provided new information of the molecular mechanisms that contribute to neurodegenerative disorders. Numerous reports have documented that ncRNAs have important contributions to several biological processes associated with the increase of neurodegenerative disorders. In addition, microRNAs (miRNAs), circular RNAs (circRNAs), as well as, long ncRNAs (lncRNAs) represent ncRNAs subtypes with the usual dysregulation in neurodegenerative disorders. Dysregulating ncRNAs has been associated with inhibiting or stimulating apoptosis in neurodegenerative disorders. Therefore, this review highlighted several ncRNAs linked to apoptosis in neurodegenerative disorders. CircRNAs, lncRNAs, and miRNAs were also illustrated completely regarding the respective signaling pathways of apoptosis.

Maternal bisphenol A (BPA) exposure has been reported to cause learning and memory deficits in born offspring. However, little is known that this impairment is potentially caused by epigenetic modulation on the development of NMDA receptor subunits. This study investigates the effect of prenatal BPA exposure on the hippocampal miR-19a and miR-539, which are responsible for regulating NMDA receptor subunits as well as learning and memory functions. Pregnant Sprague Dawley rats were orally administered with 5 mg/kg/day of BPA from pregnancy day 1 (PD1) until gestation day 21 (GD21), while control mothers received no BPA. The mothers were observed daily until GD21 for either a cesarean section or spontaneous delivery. The male offspring were sacrificed when reaching GD21 (fetus), postnatal days 7, 14, 21 (PND7, 14, 21) and adolescent age 35 (AD35) where their hippocampi were dissected from the brain. The expression of targeted miR-19a, miR-539, GRIN2A, and GRIN2B were determined by qRT-PCR while the level of GluN2A and GluN2B were estimated by western blot. At AD35, the rats were assessed with neurobehavioral tests to evaluate their learning and memory function. The findings showed that prenatal BPA exposure at 5 mg/kg/day significantly reduces the expression of miR-19a, miR-539, GRIN2A, and GRIN2B genes in the male rat hippocampus at all ages. The level of GluN2A and GluN2B proteins is also significantly reduced when reaching adolescent age. Consequently, the rats showed spatial and fear memory impairments when reaching AD35. In conclusion, prenatal BPA exposure disrupts the role of miR-19a and miR-539 in regulating the NMDA receptor subunit in the hippocampus which may be one of the causes of memory and learning impairment in adolescent rats.

The aim of this review is to systematically summarize and analyze the noncoding RNAs (ncRNAs), especially microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), in the cell apoptosis among Alzheimer's disease (AD) in recent years to demonstrate their value in the diagnosis and treatment of AD.

We systematically summarized in vitro and in vivo studies focusing on the ncRNAs in the regulation of cell apoptosis among AD in PubMed, ScienceDirect, and Google Scholar.

We discover three patterns of ncRNAs (including 'miRNA-mRNA', 'lncRNA-miRNA-mRNA', and 'circRNA-miRNA-mRNA') form the ncRNA-based regulatory networks in regulating cell apoptosis in AD.

This review provides a future diagnosis and treatment strategy for AD patients based on ncRNAs.

MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with mRNA and participate in posttranscriptional regulation of genes, resulting in reduced expression of target proteins, affecting the development, growth, aging, metabolism, and other physiological and pathological processes of animals and plants. It is a powerful negative regulator of gene expression. It mediates the information exchange between different cellular pathways in cellular homeostasis and stress response and regulates the differentiation, plasticity, and neurotransmission of neurons. In neurodegenerative diseases, in addition to the complex interactions between genetic susceptibility and environmental factors, miRNAs can serve as a promising diagnostic tool for diseases. They can also increase or reduce neuronal damage by regulating the body's signaling pathways, immune system, stem cells, gut microbiota, etc. They can not only affect the occurrence of diseases and exacerbate disease progression but also promote neuronal repair and reduce apoptosis, to prevent and slow down the development of diseases. This article reviews the research progress of miRNAs on the mechanism and treatment of neurodegenerative diseases in the nervous system. This trial is registered with NCT01819545, NCT02129452, NCT04120493, NCT04840823, NCT02253732, NCT02045056, NCT03388242, NCT01992029, NCT04961450, NCT03088839, NCT04137926, NCT02283073, NCT04509271, NCT02859428, and NCT05243017.

Alzheimer's disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and β-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3β, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aβ pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed.

Methamphetamine (METH) is an amphetamine-type stimulant that is highly toxic to the central nervous system (CNS). Repeated intake of METH can lead to addiction, which has become a globalized problem, resulting in multiple public health and safety problems. Recently, the non-coding RNA (ncRNA) has been certified to play an essential role in METH addiction through various mechanisms. Herein, we mainly focused on three kinds of ncRNAs including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), which are involved in neurotoxicity effects such as cognitive impairment, behavioral abnormalities, and psychiatric disorders due to METH abuse. In addition, differential expression (DE) ncRNAs also suggest that specific responses and sensitivity to METH neurotoxicity exist in different brain regions and cells. We summarized the relationships between the ncRNAs and METH-induced neurotoxicity and psychiatric disturbances, respectively, hoping to provide new perspectives and strategies for the prevention and treatment of METH abuse. Schematic diagram of the non-coding RNAs (ncRNAs) was involved in methamphetamine (METH)-induced neurotoxicity. The ncRNAs were involved in METH-induced blood-brain barrier disruption, neuronal, astrocyte, and microglial damage, and synaptic neurotransmission impairment. The study of ncRNAs is a hot spot in the future to further understand the neurotoxicity of METH and provide more favorable scientific support for clinical diagnosis and innovation of related treatments.

Neurodegenerative diseases manifest as progressive loss of neuronal structures and their myelin sheaths and lead to substantial morbidity and mortality, especially in the elderly. Despite extensive research, there are few effective treatment options for the diseases. MicroRNAs have been shown to be involved in the developmental processes of the central nervous system. Mounting evidence suggest they play an important role in the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, there are few reviews regarding the roles of miRNAs in neurodegenerative diseases. This review summarizes the recent developments in the roles of microRNAs in neurodegenerative diseases and presents the application of microRNA-based methods in the early diagnosis of these diseases.

Today, growing evidence indicates that patients with type 2 diabetes (T2D) are at a higher risk of developing Alzheimer's disease (AD). Indeed, AD as one of the main causes of dementia in people aged more than 65 years can be aggravated by insulin resistance (IR) and other metabolic risk factors related to T2D which are also linked to the function of the brain. Remarkably, a new term called "type 3 diabetes" has been suggested for those people who are diagnosed with AD while also showing the symptoms of IR and T2D. In this regard, the role of genetic and epigenetic changes associated with AD has been confirmed by many studies. On the other hand, it should be noted that the insulin signaling pathway is highly regulated by various mechanisms, including epigenetic factors. Among these, the role of noncoding RNAs (ncRNAs), including microRNAs and long noncoding RNAs has been comprehensively studied with respect to the pathology of AD and the most well-known underlying mechanisms. Nevertheless, the number of studies exploring the association between ncRNAs and the downstream targets of the insulin signaling pathway in the development of AD has notably increased in recent years. With this in view, the present study aimed to review the interplay between different ncRNAs and the insulin signaling pathway targets in the pathogenesis of AD to find a new approach in the field of combining biomarkers or therapeutic targets for this disease.

Emerging evidence demonstrates association of Alzheimer's disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD.

We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology.

Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques+neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs.

Significant (p < 0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ+ AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology.

Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.

Cardiovascular risk factors and biologic sex play a role in vascular dementia which is characterized by progressive reduction in cognitive function and memory. Yet, we lack understanding about the role sex plays in the molecular mechanisms whereby lipid stress contributes to cognitive decline. Five-week-old low-density lipoprotein deficient (LDL-R -/-) male and female mice and C57BL/6J wild types (WT) were fed a control or Western Diet for 8 weeks. Differential expression of protein coding and non-protein coding genes (DEG) were determined in laser captured hippocampal microvessels using genome-wide microarray, followed by bioinformatic analysis of gene networks, pathways, transcription factors and sex/gender-based analysis (SGBA). Cognitive function was assessed by Y-maze. Bioinformatic analysis revealed more DEGs in females (2412) compared to males (1972). Hierarchical clusters revealed distinctly different sex-specific gene expression profiles irrespective of diet and genotype. There were also fewer and different biologic responses in males compared to females, as well as different cellular pathways and gene networks (favoring greater neuroprotection in females), together with sex-specific transcription factors and non-protein coding RNAs. Hyperlipidemic stress also resulted in less severe cognitive dysfunction in females. This sex-specific pattern of differential hippocampal microvascular RNA expression might provide therapeutic targets for dementia in males and females.

This study was designed to test whether the Cronobacter sakazakii infection-impaired contextual learning and memory are mediated by the activation of the complement system; subsequent activation of inflammatory signals leads to alternations in serotonin transporter (SERT). To test this, rat pups (postnatal day, PND 15) were treated with either C. sakazakii (10⁷ CFU) or Escherichia coli OP50 (10⁷ CFU) or Luria bertani broth (100 μL) through oral gavage and allowed to stay with their mothers until PND 24. Experimental groups' rats were allowed to explore (PNDs 31-35) and then trained in contextual learning task (PNDs 36-43). Five days after training, individuals were tested for memory retention (PNDs 49-56). Observed behavioural data showed that C. sakazakii infection impaired contextual-associative learning and memory. Furthermore, our analysis showed that C. sakazakii infection activates complement system complement anaphylatoxin (C5a) (a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)) and mitogen-activated protein kinase kinase1 (MEKK1). Subsequently, MEKK1 induces pro-inflammatory signals possibly through apoptosis signal-regulating kinase-1 (ASK-1), c-Jun N-terminal kinase (JNK1/3) and protein kinase B gamma (AKT-3). In parallel, activated nuclear factor kappa-light-chain-enhancer B cells (NF-κB) induces interleukin-6 (IL-6) and IFNα-1, which may alter the level of serotonin transporter (SERT). Observed results suggest that impaired contextual learning and memory could be correlated with C5a-mediated NF-κβ and ASK1 pathways.