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Zheng YN, Wang Y, Chen L, Xu LZ, Zhang L, Wang JL, Liu J, Zhang QL, Yuan QL. Increased expression of the neuroplastin 65 protein is involved in neurofibrillary tangles and amyloid beta plaques in Alzheimer’s disease. World J Psychiatry 2025; 15:105751. [DOI: 10.5498/wjp.v15.i6.105751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 04/02/2025] [Accepted: 04/27/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND Alzheimer’s disease (AD) is a progressive neurodegenerative disorder currently lacking effective therapeutic interventions. Pathological hallmarks of AD include intracellular neurofibrillary tangles (NFTs) and extracellular amyloid beta (Aβ) plaques. Neuroplastin 65 (NP65), highly expressed in the brain, has been previously shown to mitigate cognitive impairments and decrease Aβ plaques in the AD mouse model, suggesting that NP65 is involved in AD neuropathology. However, direct evidence linking NP65 expression to AD pathogenesis in human brain remains absent.
AIM To quantify NP65 isoform expression gradients across distinct neuroanatomical regions in the healthy brain and investigate the alterations of NP65 expression in the AD brain.
METHODS Immunohistochemical, immunofluorescent and western blot analyses were used to investigate NP65 expression in 19 postmortem brains (AD = 10, controls = 9). Double immunostaining with 6E10 and or phosphorylated-microtubule-associated protein tau (AT-8, a marker for NFT) markers was performed to assess NP65 colocalization with Aβ plaques and NFTs.
RESULTS In controls, NP65 was highly expressed in a wide-range of brain areas. AD cases showed significantly increased NP65 immunoreactivity across multiple brain regions, including the frontal and temporal cortex, hippocampus, and cerebellum, compared to controls. Western blot analysis consistently confirmed significantly elevated NP65 expression in the hippocampus of AD patients relative to controls. Double immunostaining demonstrated partial colocalization of NP65 with NFTs and Aβ plaques in AD brain tissue.
CONCLUSION Our findings demonstrate a significant increase of NP65 protein, which colocalizes with NFTs and Aβ plaques in AD brains, providing direct evidence supporting a critical role of NP65 expression in the neuropathological mechanisms of this disease.
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Affiliation(s)
- Ya-Ni Zheng
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
| | - Yan Wang
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha 410013, Hunan Province, China
| | - Ling Chen
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
| | - Li-Zhang Xu
- Department of Orthopaedics, Xiangan Hospital, Xiamen University, Xiamen 361102, Fujian Province, China
| | - Lei Zhang
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
| | - Jia-Lu Wang
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
| | - Juan Liu
- Chinese Institute for Brain Research, Beijing 100000, China
| | - Qi-Lei Zhang
- Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha 410013, Hunan Province, China
- Department of Anatomy and Neurobiology, Changsha Medical University, Changsha 410013, Hunan Province, China
| | - Qiong-Lan Yuan
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai 200092, China
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai 200092, China
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Dolgacheva LP, Zinchenko VP, Nadeev AD, Goncharov NV. Serotonergic Regulation in Alzheimer's Disease. Int J Mol Sci 2025; 26:5218. [PMID: 40508026 PMCID: PMC12154332 DOI: 10.3390/ijms26115218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2025] [Revised: 05/18/2025] [Accepted: 05/27/2025] [Indexed: 06/16/2025] Open
Abstract
Serotonin (5-HT) is a neurotransmitter that also plays an important role in the regulation of vascular tone and angiogenesis. This review focuses on the involvement of the 5-HT system in pathological processes leading to the development of Alzheimer's disease (AD). There is evidence that damage or dysfunction of the 5-HT system contributes to the development of AD, and different subtypes of 5-HT receptors are a potential target for the treatment of AD. A link has been established between AD, depression, stress, and 5-HT deficiency in the brain. There are new data on the role of circadian rhythms in modulating stress, depression, and the 5-HT system; amyloid β (Aβ) plaque clearance; and AD progression. Circadian disruption inhibits Aβ plaque clearance and modulates AD progression. The properties and functions of 5-HT, its receptors, and serotonergic neurons are presented. Special attention is paid to the central role of 5-HT in brain development, including neurite outgrowth, regulation of somatic morphology, motility, synaptogenesis, control of dendritic spine shape and density, neuronal plasticity determining its role in network regeneration, and changes in innervation after brain damage. The results of different studies indicate that the interaction of amyloid β oligomers (AβO) with mitochondria is a sufficient trigger for AD-related neurodegeneration. The action of 5-HT leads to an improvement in mitochondrial quality and the restoration of brain areas after traumatic brain injury, chronic stress, or developmental disorders in AD. The role of a healthy lifestyle and drugs acting on serotonin receptors in the prevention and treatment of AD is discussed.
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Affiliation(s)
- Lyudmila P. Dolgacheva
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Valery P. Zinchenko
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Alexander D. Nadeev
- Federal Research Center “Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences”, Institute of Cell Biophysics of the Russian Academy of Sciences, Pushchino 142290, Russia (V.P.Z.)
| | - Nikolay V. Goncharov
- Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Saint Petersburg 194223, Russia
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Cheng J, Chen L, Zheng YN, Liu J, Zhang L, Zhang XM, Huang L, Yuan QL. Disfunction of dorsal raphe nucleus-hippocampus serotonergic-HTR3 transmission results in anxiety phenotype of Neuroplastin 65-deficient mice. Acta Pharmacol Sin 2024; 45:1393-1405. [PMID: 38528118 PMCID: PMC11192762 DOI: 10.1038/s41401-024-01252-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 02/26/2024] [Indexed: 03/27/2024]
Abstract
Anxiety disorders are the most common psychiatric condition, but the etiology of anxiety disorders remains largely unclear. Our previous studies have shown that neuroplastin 65 deficiency (NP65-/-) mice exhibit abnormal social and mental behaviors and decreased expression of tryptophan hydroxylase 2 (TPH2) protein. However, whether a causal relationship between TPH2 reduction and anxiety disorders exists needs to be determined. In present study, we found that replenishment of TPH2 in dorsal raphe nucleus (DRN) enhanced 5-HT level in the hippocampus and alleviated anxiety-like behaviors. In addition, injection of AAV-NP65 in DRN significantly increased TPH2 expression in DRN and hippocampus, and reduced anxiety-like behaviors. Acute administration of exogenous 5-HT or HTR3 agonist SR57227A in hippocampus mitigated anxiety-like behaviors in NP65-/- mice. Moreover, replenishment of TPH2 in DRN partly repaired the impairment of long-term potentiation (LTP) maintenance in hippocampus of NP65-/- mice. Finally, we found that loss of NP65 lowered transcription factors Lmx1b expression in postnatal stage and replenishment of NP65 in DRN reversed the decrease in Lmx1b expression of NP65-/- mice. Together, our findings reveal that NP65 deficiency induces anxiety phenotype by downregulating DRN-hippocampus serotonergic-HTR3 transmission. These studies provide a novel and insightful view about NP65 function, suggesting an attractive potential target for treatment of anxiety disorders.
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Affiliation(s)
- Jie Cheng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Ling Chen
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Ya-Ni Zheng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Juan Liu
- Chinese Institute for Brain Research, Beijing, 102206, China
| | - Lei Zhang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Xiao-Ming Zhang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Liang Huang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Qiong-Lan Yuan
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200065, China.
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, 200092, China.
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4
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Akotkar L, Aswar U, Ganeshpurkar A, Rathod K, Bagad P, Gurav S. Phytoconstituents Targeting the Serotonin 5-HT 3 Receptor: Promising Therapeutic Strategies for Neurological Disorders. ACS Pharmacol Transl Sci 2024; 7:1694-1710. [PMID: 38898946 PMCID: PMC11184608 DOI: 10.1021/acsptsci.4c00084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024]
Abstract
The 5-hydroxytryptamine-3 receptor (5-HT3R), a subtype of serotonin receptor, is a ligand-gated ion channel crucial in mediating fast synaptic transmission in the central and peripheral nervous systems. This receptor significantly influences various neurological activities, encompassing neurotransmission, mood regulation, and cognitive processing; hence, it may serve as an innovative target for neurological disorders. Multiple studies have revealed promising results regarding the beneficial effects of these phytoconstituents and extracts on conditions such as nausea, vomiting, neuropathic pain depression, anxiety, Alzheimer's disease, cognition, epilepsy, sleep, and dyskinesia via modulation of 5-HT3R in the pathophysiology of neurological disorder. The review delves into a detailed exploration of in silico, in vitro, and in vivo studies and clinical studies that discussed phytoconstituents acting on 5-HT3R and attenuates difficulties in neurological diseases. The diverse mechanisms by which plant-derived phytoconstituents influence 5-HT3R activity offer exciting avenues for developing innovative therapeutic interventions. Besides producing an agonistic or antagonistic effect, some phytoconstituents exert modulatory effects on 5-HT3R activity through multifaceted mechanisms. These include γ-aminobutyric acid and cholinergic neuronal pathways, interactions with neurokinin (NK)-1, NK2, serotonergic, and γ-aminobutyric acid(GABA)ergic systems, dopaminergic influences, and mediation of calcium ions release and inflammatory cascades. Notably, the phytoconstituent's capacity to reduce oxidative stress has also emerged as a significant factor contributing to their modulatory role. Despite the promising implications, there is currently a dearth of exploration needed to understand the effect of phytochemicals on the 5-HT3R. Comprehensive preclinical and clinical research is of the utmost importance to broaden our knowledge of the potential therapeutic benefits associated with these substances.
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Affiliation(s)
- Likhit Akotkar
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Urmila Aswar
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Ankit Ganeshpurkar
- Department
of Pharmaceutical Chemistry, Poona College
of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune411038, India
| | - Kundlik Rathod
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Pradnya Bagad
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Shailendra Gurav
- Department
of Pharmacognosy, Goa College of Pharmacy, Goa University, Goa 403001, India
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Lee B, Yu MS, Song JG, Lee HM, Kim HW, Na D. Corydalis ternata Nakai Alleviates Cognitive Decline in Alzheimer's Disease by Reducing β-Amyloid and Neuroinflammation. Rejuvenation Res 2024; 27:87-101. [PMID: 38545769 DOI: 10.1089/rej.2023.0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2024] Open
Abstract
Recently, natural herbs have gained increasing attention owing to their comparatively low toxicity levels and the abundance of historical medical documentation regarding their use. Nevertheless, owing to a lack of knowledge regarding these herbs and their compounds, attempts to find those that could be beneficial for treating diseases have often been ad hoc; thus, there is now a growing demand for an in silico method to identify beneficial herbs. In this study, we present a computational approach for identifying natural herbs specifically effective in treating cognitive decline in Alzheimer's disease (AD) sufferers, which analyzes the similarities between herbal compounds and known drugs targeting AD-related proteins. Our in silico method suggests that Corydalis ternata can improve cognitive decline in AD sufferers. Behavioral tests with an AD mouse model for the confirmation of the in silico prediction reveals that C. ternata significantly alleviated the cognitive decline (memory and motor functions) caused by neurodegeneration. Further pathology analyses reveal that C. ternata decreases the level of Aβ plaques, reduces neuroinflammation, and promotes autophagy flux, and thus C. ternata can be clinically effective for preventing mild cognitive impairment during the early stages of AD. These findings highlight the potential utility of our in silico method and the potential clinical application of the identified natural herb in treating and preventing AD.
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Affiliation(s)
- Bomi Lee
- Department of Bio-Integrated Science and Technology, College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Myeong-Sang Yu
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Jae Gwang Song
- Department of Bio-Integrated Science and Technology, College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Hyang-Mi Lee
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
| | - Hyung Wook Kim
- Department of Bio-Integrated Science and Technology, College of Life Sciences, Sejong University, Seoul, Republic of Korea
| | - Dokyun Na
- Department of Biomedical Engineering, Chung-Ang University, Seoul, Republic of Korea
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Sheng M, Yu L, Peng Y, Wang Q, Huang J, Yang X. Combination of Ternary Electrochemiluminescence System of BNQDs/AgMOG-K 2S 2O 8 and Electrochemiluminescence Resonance Energy Transfer Strategy for Ultrasensitive Immunoassay of Amyloid-β Protein. Anal Chem 2024; 96:41-48. [PMID: 38100715 DOI: 10.1021/acs.analchem.3c02545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2023]
Abstract
In this work, based on boron nitride quantum dots (BNQDs) as energy donors and MnO2@MWCNTs-COOH as energy receptors, we designed an efficient electrochemiluminescence resonance energy transfer (ECL-RET) immunosensor for the detection of amyloid-β (Aβ42) protein, a biomarker of Alzheimer's disease (AD). First, the signal amplification of a ternary ECL system composed of BNQDs (as the ECL emitter), K2S2O8 (as the coreactant), and silver metal-organic gels (AgMOG, as the coreaction accelerator) was realized, and PDDA as stabilizer was added, a strong and stable initial ECL signal was obtained. AgMOG could not only support a large amount of BNQDs and Aβ42 capture antibody (Ab1) through Ag-N bond but also exhibit excellent ECL catalytic performance and enhance the luminescent intensity of BNQDs@PDDA-K2S2O8 system. In addition, due to the broad absorption spectrum of MnO2@MWCNTs-COOH and the extensive overlap with the ECL emission spectrum of BNQDs, the quenching probe Ab2-MnO2@MWCNTs-COOH could be introduced into the ternary system through a sandwich immune response. On this basis, the signal on-off ECL immunosensor was constructed to achieve the ultrasensitive detection of Aβ42 through signal transformation. Under the optimal conditions, the prepared ECL biosensor manifested a wide linear range (10 fg/mL-100 ng/mL) with a detection limit of 2.89 fg/mL and showed excellent stability, selectivity, and repeatability, which provided an effective strategy for the ultrasensitive detection of biomarkers in clinical analysis.
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Affiliation(s)
- Mengting Sheng
- Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Linying Yu
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Changchun, Jilin 130022, China
| | - Yao Peng
- Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Qian Wang
- Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
| | - Jianshe Huang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Changchun, Jilin 130022, China
| | - Xiurong Yang
- Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Changchun, Jilin 130022, China
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7
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Wu DD, Cheng J, Zheng YN, Liu YT, Hou SX, Liu LF, Huang L, Yuan QL. Neuroplastin 65 deficiency reduces amyloid plaque formation and cognitive deficits in an Alzheimer's disease mouse model. Front Cell Neurosci 2023; 17:1129773. [PMID: 37213217 PMCID: PMC10196121 DOI: 10.3389/fncel.2023.1129773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 04/17/2023] [Indexed: 05/23/2023] Open
Abstract
Introduction Alzheimer's disease (AD) is characterized by increasing cognitive dysfunction, progressive cerebral amyloid beta (Aβ) deposition, and neurofibrillary tangle aggregation. However, the molecular mechanisms of AD pathologies have not been completely understood. As synaptic glycoprotein neuroplastin 65 (NP65) is related with synaptic plasticity and complex molecular events underlying learning and memory, we hypothesized that NP65 would be involved in cognitive dysfunction and Aβ plaque formation of AD. For this purpose, we examined the role of NP65 in the transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD. Methods Neuroplastin 65-knockout (NP65-/-) mice crossed with APP/PS1 mice to get the NP65-deficient APP/PS1 mice. In the present study, a separate cohort of NP65-deficient APP/PS1 mice were used. First, the cognitive behaviors of NP65-deficient APP/PS1 mice were assessed. Then, Aβ plaque burden and Aβ levels in NP65-deficient APP/PS1 mice were measured by immunostaining and western blot as well as ELISA. Thirdly, immunostaining and western blot were used to evaluate the glial response and neuroinflammation. Finally, protein levels of 5-hydroxytryptamin (serotonin) receptor 3A and synaptic proteins and neurons were measured. Results We found that loss of NP65 alleviated the cognitive deficits of APP/PS1 mice. In addition, Aβ plaque burden and Aβ levels were significantly reduced in NP65-deficient APP/PS1 mice compared with control animals. NP65-loss in APP/PS1 mice resulted in a decrease in glial activation and the levels of pro- and anti-inflammatory cytokines (IL-1β, TNF-α, and IL-4) as well as protective matrix YM-1 and Arg-1, but had no effect on microglial phenotype. Moreover, NP65 deficiency significantly reversed the increase in 5-hydroxytryptamine (serotonin) receptor 3A (Htr3A) expression levels in the hippocampus of APP/PS1 mice. Discussion These findings identify a previously unrecognized role of NP65 in cognitive deficits and Aβ formation of APP/PS1 mice, and suggest that NP65 may serve as a potential therapeutic target for AD.
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Affiliation(s)
- Dan-Dan Wu
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jie Cheng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Ya-Ni Zheng
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yu-Tong Liu
- Department of Radiology, University of Nebraska Medical Center, Omaha, NE, United States
| | - Shuang-Xin Hou
- Department of Neurobiology, Shanghai Pudong Hospital, Fudan University, Shanghai, China
| | - Li-Fen Liu
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
| | - Liang Huang
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, China
| | - Qiong-Lan Yuan
- Department of Neurology, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Human Anatomy, Histology and Embryology, Tongji University School of Medicine, Shanghai, China
- *Correspondence: Qiong-Lan Yuan,
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