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Regulator of G protein signaling 6 mediates exercise-induced recovery of hippocampal neurogenesis,learning,and memory in a mouse model of Alzheimer’s disease
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作者 Mackenzie M.Spicer Jianqi Yang +5 位作者 Daniel Fu Alison N.DeVore Marisol Lauffer Nilufer S.Atasoy Deniz Atasoy Rory A.Fisher 《Neural Regeneration Research》 SCIE CAS 2025年第10期2969-2981,共13页
Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rode... Hippocampal neuronal loss causes cognitive dysfunction in Alzheimer’s disease.Adult hippocampal neurogenesis is reduced in patients with Alzheimer’s disease.Exercise stimulates adult hippocampal neurogenesis in rodents and improves memory and slows cognitive decline in patients with Alzheimer’s disease.However,the molecular pathways for exercise-induced adult hippocampal neurogenesis and improved cognition in Alzheimer’s disease are poorly understood.Recently,regulator of G protein signaling 6(RGS6)was identified as the mediator of voluntary running-induced adult hippocampal neurogenesis in mice.Here,we generated novel RGS6fl/fl;APP_(SWE) mice and used retroviral approaches to examine the impact of RGS6 deletion from dentate gyrus neuronal progenitor cells on voluntary running-induced adult hippocampal neurogenesis and cognition in an amyloid-based Alzheimer’s disease mouse model.We found that voluntary running in APP_(SWE) mice restored their hippocampal cognitive impairments to that of control mice.This cognitive rescue was abolished by RGS6 deletion in dentate gyrus neuronal progenitor cells,which also abolished running-mediated increases in adult hippocampal neurogenesis.Adult hippocampal neurogenesis was reduced in sedentary APP_(SWE) mice versus control mice,with basal adult hippocampal neurogenesis reduced by RGS6 deletion in dentate gyrus neural precursor cells.RGS6 was expressed in neurons within the dentate gyrus of patients with Alzheimer’s disease with significant loss of these RGS6-expressing neurons.Thus,RGS6 mediated voluntary running-induced rescue of impaired cognition and adult hippocampal neurogenesis in APP_(SWE) mice,identifying RGS6 in dentate gyrus neural precursor cells as a possible therapeutic target in Alzheimer’s disease. 展开更多
关键词 adult hippocampal neurogenesis alzheimer’s disease dentate gyrus EXERCISE learning/memory neural precursor cells regulator of G protein signaling 6(RGS6)
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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease
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作者 Yinglong Miao Michael S.Wolfe 《Neural Regeneration Research》 SCIE CAS 2025年第1期174-180,共7页
γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the ... γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms ofγ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer’s disease and perhaps Alzheimer’s disease in general. 展开更多
关键词 alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics NOTCH
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Lamotrigine protects against cognitive deficits,synapse and nerve cell damage,and hallmark neuropathologies in a mouse model of Alzheimer’s disease 被引量:1
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作者 Xin-Xin Fu Rui Duan +7 位作者 Si-Yu Wang Qiao-Quan Zhang Bin Wei Ting Huang Peng-Yu Gong Yan E Teng Jiang Ying-Dong Zhang 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第1期189-193,共5页
Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular me... Lamotrigine(LTG)is a widely used drug for the treatment of epilepsy.Emerging clinical evidence suggests that LTG may improve cognitive function in patients with Alzheimer’s disease.However,the underlying molecular mechanisms remain unclear.In this study,amyloid precursor protein/presenilin 1(APP/PS1)double transgenic mice were used as a model of Alzheimer’s disease.Five-month-old APP/PS1 mice were intragastrically administered 30 mg/kg LTG or vehicle once per day for 3 successive months.The cognitive functions of animals were assessed using Morris water maze.Hyperphosphorylated tau and markers of synapse and glial cells were detected by western blot assay.The cell damage in the brain was investigated using hematoxylin and eosin staining.The levels of amyloid-βand the concentrations of interleukin-1β,interleukin-6 and tumor necrosis factor-αin the brain were measured using enzyme-linked immunosorbent assay.Differentially expressed genes in the brain after LTG treatment were analyzed by high-throughput RNA sequencing and real-time polymerase chain reaction.We found that LTG substantially improved spatial cognitive deficits of APP/PS1 mice;alleviated damage to synapses and nerve cells in the brain;and reduced amyloid-βlevels,tau protein hyperphosphorylation,and inflammatory responses.High-throughput RNA sequencing revealed that the beneficial effects of LTG on Alzheimer’s disease-related neuropathologies may have been mediated by the regulation of Ptgds,Cd74,Map3k1,Fosb,and Spp1 expression in the brain.These findings revealed potential molecular mechanisms by which LTG treatment improved Alzheimer’s disease.Furthermore,these data indicate that LTG may be a promising therapeutic drug for Alzheimer’s disease. 展开更多
关键词 alzheimer’s disease alzheimer’s disease-related neuropathologies amyloid-βpathology APP/PS1 mice cognitive deficits damage of synapses and nerve cells high-throughput RNA sequencing LAMOTRIGINE neuroinflammation tau protein hyperphosphorylation
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Inhibiting 5-hydroxytryptamine receptor 3 alleviates pathological changes of a mouse model of Alzheimer's disease 被引量:1
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作者 Li-Fen Liu Yu-Tong Liu +5 位作者 Dan-Dan Wu Jie Cheng Na-Na Li Ya-Ni Zheng Liang Huang Qiong-Lan Yuan 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第9期2019-2028,共10页
Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In... Extracellular amyloid beta(Aβ) plaques are main pathological feature of Alzheimer’s disease.However,the specific type of neuro ns that produce Aβ peptides in the initial stage of Alzheimer’s disease are unknown.In this study,we found that 5-hydroxytryptamin receptor 3A subunit(HTR3A) was highly expressed in the brain tissue of transgenic amyloid precursor protein and presenilin-1 mice(an Alzheimer’s disease model) and patients with Alzheimer’s disease.To investigate whether HTR3A-positive interneurons are associated with the production of Aβ plaques,we performed double immunostaining and found that HTR3A-positive interneurons were clustered around Aβ plaques in the mouse model.Some amyloid precursor protein-positive or β-site amyloid precursor protein cleaving enzyme-1-positive neurites near Aβ plaques were co-localized with HTR3A interneurons.These results suggest that HTR3A-positive interneurons may partially contribute to the generation of Aβ peptides.We treated 5.0-5.5-month-old model mice with tro pisetron,a HTR3 antagonist,for 8 consecutive weeks.We found that the cognitive deficit of mice was partially reversed,Aβ plaques and neuroinflammation we re remarkably reduced,the expression of HTR3 was remarkably decreased and the calcineurin/nuclear factor of activated T-cell 4 signaling pathway was inhibited in treated model mice.These findings suggest that HTR3A interneurons partly contribute to generation of Aβ peptide at the initial stage of Alzheimer’s disease and inhibiting HTR3 partly reve rses the pathological changes of Alzheimer’s disease. 展开更多
关键词 5-hydroxytryptamin receptor 3 alzheimer’s disease amyloid beta plaques CALCINEURIN cognitive deficits HTR3 interneurons iCa2+ nuclear factor of activated T-cells transgenic amyloid precursor protein and presenilin-1 mice TROPISETRON
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阿尔茨海默病(Alzheimer’s Disease,AD)与动力相关蛋白1(dynamin-related protein 1,Drp1) 被引量:1
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作者 李华 龙建纲 刘健康 《生物学杂志》 CAS CSCD 2013年第2期68-72,共5页
阿尔茨海默病(AD)已成为威胁老年人生活的一种常见病,对老年人的生活质量有着严重的影响,目前尚无有效地防治方法。最新研究发现在阿尔茨海默病的病理发生中,神经细胞伴有显著的线粒体代谢紊乱和动态变化的异常,其中动力相关蛋白1(Drp1... 阿尔茨海默病(AD)已成为威胁老年人生活的一种常见病,对老年人的生活质量有着严重的影响,目前尚无有效地防治方法。最新研究发现在阿尔茨海默病的病理发生中,神经细胞伴有显著的线粒体代谢紊乱和动态变化的异常,其中动力相关蛋白1(Drp1)是参与线粒体动态变化的关键分子。深入研究阿尔茨海默病中线粒体动态变化的异常及Drp1等关键分子的作用机制,对于揭示AD的发生机制及寻找药物作用靶点具有重要意义。综述了Drp1在阿尔茨海默病中的调控机制。 展开更多
关键词 阿尔茨海默病(AD) 动力相关蛋白1(Drp1) 线粒体
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Calycosin improves cognitive function in a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway 被引量:27
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作者 Lei Song Xiaoping Li +2 位作者 Xiao-xue Bai Jian Gao Chun-yan Wang 《Neural Regeneration Research》 SCIE CAS CSCD 2017年第11期1870-1876,共7页
The major pathological changes in Alzheimer's disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produc... The major pathological changes in Alzheimer's disease are beta amyloid deposits and cognitive impairment. Calycosin is a typical phy- toestrogen derived from radix astragali that binds to estrogen receptors to produce estrogen-like effects. Radix astragali Calycosin has been shown to relieve cognitive impairment induced by diabetes mellitus, suggesting calycosin may improve the cognitive function of Alzhei- mer's disease patients. The protein kinase C pathway is upstream of the mitogen-activated protein kinase pathway and exerts a neuropro- tective effect by regulating Alzheimer's disease-related beta amyloid degradation. We hypothesized that calycosin improves the cognitive function of a transgenic mouse model of Alzheimer's disease by activating the protein kinase C pathway. Various doses of calycosin (10, 20 and 40 mg/kg) were intraperitoneally injected into APP/PS1 transgenic mice that model Alzheimer's disease. Calycosin diminished hippocampal beta amyloid, Tau protein, interleukin-lbeta, tumor necrosis factor-alpha, acetylcholinesterase and malondialdehyde levels in a dose-dependent manner, and increased acetylcholine and glutathione activities. The administration of a protein kinase C inhibitor, cal- phostin C, abolished the neuroprotective effects of calycosin including improving cognitive ability, and anti-oxidative and anti-inflammato- ry effects. Our data demonstrated that calycosin mitigated oxidative stress and inflammatory responses in the hippocampus of Alzheimer's disease model mice by activating the protein kinase C pathway, and thereby improving cognitive function. 展开更多
关键词 nerve regeneration NEURODEGENERATION alzheimer's disease CALYCOSIN HIPPOCAMPUS oxidative stress inflammation mice protein kinase C calphostin C GLUTATHIONE MALONDIALDEHYDE neural regeneration
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Mutations of beta-amyloid precursor protein alter the consequence of Alzheimer's disease pathogenesis 被引量:8
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作者 Nuo-Min Li Ke-Fu Liu +3 位作者 Yun-Jie Qiu Huan-Huan Zhang Hiroshi Nakanishi Hong Qing 《Neural Regeneration Research》 SCIE CAS CSCD 2019年第4期658-665,共8页
Alzheimer's disease is pathologically defined by accumulation of extracellular amyloid-β(Aβ). Approximately 25 mutations in β-amyloid precursor protein(APP) are pathogenic and cause autosomal dominant Alzheimer... Alzheimer's disease is pathologically defined by accumulation of extracellular amyloid-β(Aβ). Approximately 25 mutations in β-amyloid precursor protein(APP) are pathogenic and cause autosomal dominant Alzheimer's disease. To date, the mechanism underlying the effect of APP mutation on Aβ generation is unclear. Therefore, investigating the mechanism of APP mutation on Alzheimer's disease may help understanding of disease pathogenesis. Thus, APP mutations(A673T, A673 V, E682 K, E693 G, and E693Q) were transiently co-transfected into human embryonic kidney cells. Western blot assay was used to detect expression levels of APP, beta-secretase 1, and presenilin 1 in cells. Enzyme-linked immunosorbent assay was performed to determine Aβ_(1–40) and Aβ_(1–42) levels. Liquid chromatography-tandem mass chromatography was used to examine VVIAT, FLF, ITL, VIV, IAT, VIT, TVI, and VVIA peptide levels. Immunofluorescence staining was performed to measure APP and early endosome antigen 1 immunoreactivity. Our results show that the protective A673 T mutation decreases Aβ_(42)/Aβ_(40) rate by downregulating IAT and upregulating VVIA levels. Pathogenic A673 V, E682 K, and E693 Q mutations promote Aβ_(42)/Aβ_(40) rate by increasing levels of CTF99, Aβ_(42), Aβ_(40), and IAT, and decreasing VVIA levels. Pathogenic E693 G mutation shows no significant change in Aβ_(42)/Aβ_(40) ratio because of inhibition of γ-secretase activity. APP mutations can change location from the cell surface to early endosomes. Our findings confirm that certain APP mutations accelerate Aβ generation by affecting the long Aβ cleavage pathway and increasing Aβ_(42/40) rate, thereby resulting in Alzheimer's disease. 展开更多
关键词 nerve REGENERATION alzheimer’s disease Β-AMYLOID precursor protein amyloidβ APP MUTATIONS liquid chromatography-tandem mass CHROMATOGRAPHY cellular localization long neural REGENERATION
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Compound Danshen tablets downregulate amyloid protein precursor mRNA expression in a transgenic cell model of Alzheimer's disease Effects and a comparison with donepezil 被引量:8
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作者 Ren'an Qin Desheng Zhou +4 位作者 Jiajun Wang Hua Hu Yang Yang Xiaoxuan Yao Xiaopeng Sun 《Neural Regeneration Research》 SCIE CAS CSCD 2012年第9期659-663,共5页
After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after cul... After gene mutation, the pcDNA3.1/APP595/596 plasmid was transfected into HEK293 cells to establish a cell model of Alzheimer's disease. The cell model was treated with donepezil or compound Danshen tablets after culture for 72 hours. Reverse transcription-PCR showed that the mRNA expression of amyloid protein precursor decreased in all groups following culture for 24 hours, and that there was no significant difference in the amount of decrease between donepezil and compound Danshen tablets. Our results suggest that compound Danshen tablets can reduce expression of the mRNA for amyloid protein precursor in a transgenic cell model of Alzheimer's disease, with similar effects to donepezil. 展开更多
关键词 amyloid protein precursor alzheimer’s disease transgenic cell model compound Danshen tablets Chinese medicine neural regeneration
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Genistein protects hippocampal neurons against injury by regulating calcium/calmodulin dependent protein kinase Ⅳ protein levels in Alzheimer's disease model rats 被引量:7
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作者 Shu Ye Ting-ting Wang +4 位作者 Biao Cai Yan Wang Jing Li Ji-xian Zhan Guo-ming Shen 《Neural Regeneration Research》 SCIE CAS CSCD 2017年第9期1479-1484,共6页
Genistein has a neuroprotective effect in Alzheimer's disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production o... Genistein has a neuroprotective effect in Alzheimer's disease, but its mechanism of action needs further clarification. Accumulating evidence suggests that excessive phosphorylation of tau protein causes production of neurofibrillary tangles, which is one of the main pathological characteristics of Alzheimer's disease, and tau protein can be phosphorylated by calcium/calmodulin dependent protein kinase IV (CAMK4). After 7 days of pre-administration of genistein (90 mg/kg), an Alzheimer's disease rat model was established using an intraperitoneal injection of D-galactose combined with an intracerebral injection of amyloid-β peptide (25-35). The rat was then continu- ously administered genistein (90 mg/kg) for 42 days. The Morris water maze test, western blotting and hematoxylin-eosin staining results showed that genistein significantly decreased the escape latency and increased the number of times crossing the platform, reduced p-tau, CALM, CAMKK1 and p-CAMK4 protein levels in the hippocampus, and alleviated hippocampal neuron damage. These findings indicate that genistein may play a neuroprotective role in Alzheimer's disease through regulating CAMK4 to modulate tau hyperphosphorylation. Key 展开更多
关键词 nerve regeneration NEURODEGENERATION GENISTEIN alzheimer's disease NEUROPROTECTION hippocampus learning memory tau protein CAMK4 CALM CAMKK1 neural regeneration
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Natural polyphenols effects on protein aggregates in Alzheimer's and Parkinson's prion-like diseases 被引量:3
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作者 aline freyssin guylène page +1 位作者 bernard fauconneau agnès rioux bilan 《Neural Regeneration Research》 SCIE CAS CSCD 2018年第6期955-961,共7页
Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposit... Alzheimer's and Parkinson's diseases are the most common neurodegenerative diseases. They are characterized by protein aggregates and so can be considered as prion-like disease. The major components of these deposits are amyloid peptide and tau for Alzheimer's disease, α-synuclein and synphilin-1 for Parkinson's disease. Drugs currently proposed to treat these pathologies do not prevent neurodegenerative processes and are mainly symptomatic therapies. Molecules inducing inhibition of aggregation or disaggregation of these proteins could have beneficial effects, especially if they have other beneficial effects for these diseases. Thus, several natural polyphenols, which have antioxidative, anti-inflammatory and neuroprotective properties, have been largely studied, for their effects on protein aggregates found in these diseases, notably in vitro. In this article, we propose to review the significant papers concerning the role of polyphenols on aggregation and disaggregation of amyloid peptide, tau, α-synuclein, synphilin-1, suggesting that these compounds could be useful in the treatments in Alzheimer's and Parkinson's diseases. 展开更多
关键词 natural polyphenols protein aggregates alzheimer's disease amyloid peptide amyloid plaques hyperphosphorylated tau Parkinson's disease a-synuclein synphilin-I
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Neurofibrillary tangles in Alzheimer's disease: elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics 被引量:4
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作者 athanasios metaxas stefan j.kempf 《Neural Regeneration Research》 SCIE CAS CSCD 2016年第10期1579-1581,共3页
As a key contributor to memory storage, the synapse is one of the earliest affected neuronal components in Alzheimer's disease (AD). Under physiological conditions, the synaptic con- nections between neurons underg... As a key contributor to memory storage, the synapse is one of the earliest affected neuronal components in Alzheimer's disease (AD). Under physiological conditions, the synaptic con- nections between neurons undergo activity-dependent func- tional and morphological re-organisation. This dynamic, 'plastic' neural ability critically depends on the structural integrity of the synapse. Thus, proteins that are implicated in preserving the organisation and dynamics of synaptic connections, including microtubules of the cytoskeleton and associated proteins, have attracted much focus for their involvement in the malfunction- ing AD synapse. 展开更多
关键词 Neurofibrillary tangles in alzheimer’s disease elucidation of the molecular mechanism by immunohistochemistry and tau protein phospho-proteomics NFT
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Role of Microtubule-associated Protein Tau Phosphorylation in Alzheimer's Disease 被引量:14
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作者 马荣红 张瑶 +3 位作者 洪小月 张俊菲 王建枝 刘恭平 《Journal of Huazhong University of Science and Technology(Medical Sciences)》 SCIE CAS 2017年第3期307-312,共6页
As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphoryla... As a major microtubule-associated protein, tau plays an important role in promoting microtubule assembly and stabilizing microtubules. In Alzheimer’s disease(AD) and other tauopathies, the abnormally hyperphosphorylated tau proteins are aggregated into paired helical filaments and accumulated in the neurons with the form of neurofibrillary tangles. An imbalanced regulation in protein kinases and protein phosphatases is the direct cause of tau hyperphosphorylation. Among various kinases and phosphatases, glycogen synthase kinase-3β(GSK-3β) and protein phosphatase 2A(PP2A) are the most implicated. Accumulation of the hyperphosphorylated tau induces synaptic toxicity and cognitive impairments. Here, we review the upstream factors or pathways that can regulate GSK-3β or PP2A activity mainly based on our recent findings. We will also discuss the mechanisms that may underlie tau-induced synaptic toxicity. 展开更多
关键词 alzheimer's disease TAU glycogen synthase kinase-3β protein phosphatase 2A synaptic toxicity
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Transthyretin—A Key Gene Involved in Regulating Learning and Memory in Brain, and Providing Neuroprotection in Alzheimer Disease via Neuronal Synthesis of Transthyretin Protein 被引量:1
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作者 Javed Iqbal 《Journal of Behavioral and Brain Science》 2018年第2期77-92,共16页
Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CS... Transthyretin (TTR), a carrier protein present in the liver and choroid plexus of the brain, has been shown to be responsible for binding thyroid hormone thyroxin (T4) and retinol in plasma and cerebrospinal fluid (CSF). TTR aids in sequestering of beta-amyloid peptides Aβ deposition, and protects the brain from trauma, ischemic stroke and Alzheimer disease (AD). Accordingly, hippocampal gene expression of TTR plays a significant role in learning and memory as well as in simulation of spatial memory tasks. TTR via interacting with transcription factor CREB regulates this process and decreased expression leads to memory deficits. By different signaling pathways, like MAPK, AKT, and ERK via Src, TTR provides tropical support through megalin receptor by promoting neurite outgrowth and protecting the neurons from traumatic brain injury. TTR is also responsible for the transient rise in intracellular Ca2+ via NMDA receptor, playing a dominant role under excitotoxic conditions. In this review, we tried to shed light on how TTR is involved in maintaining normal cognitive processes, its role in learning and memory, under memory deficit conditions;by which mechanisms it promotes neurite outgrowth;and how it protects the brain from Alzheimer disease (AD). 展开更多
关键词 Learning and Memory TTR—Transthyretin AD—alzheimer disease CSF—Cerebrospinal Fluid MAPK—Mitogen-Activated protein KINASES CREB—cAMP Response Element Binding protein ERK—Extracellular Receptor KINASES Aβ—Amyloid Beta LTP—Long-Term POTENTIATION LTD—Long-Term Depression
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Two memory associated genes regulated by amyloid precursor protein intracellular domain Novel insights into the pathogenesis of learning and memory impairment in Alzheimer's disease
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作者 Chuandong Zheng Xi Gu Zhimei Zhong Rui Zhu Tianming Gao Fang Wang 《Neural Regeneration Research》 SCIE CAS CSCD 2012年第5期341-346,共6页
In this study, we employed chromatin immunoprecipitation, a useful method for studying the locations of transcription factors bound to specific DNA regions in specific cells, to investigate amyloid precursor protein i... In this study, we employed chromatin immunoprecipitation, a useful method for studying the locations of transcription factors bound to specific DNA regions in specific cells, to investigate amyloid precursor protein intracellular domain binding sites in chromatin DNA from hippocampal neurons of rats, and to screen out five putative genes associated with the learning and memory functions. The promoter regions of the calcium/calmodulin-dependent protein kinase II alpha and glutamate receptor-2 genes were amplified by PCR from DNA products immunoprecipitated by amyloid precursor protein intracellular domain. An electrophoretic mobility shift assay and western blot analysis suggested that the promoter regions of these two genes associated with learning and memory were bound by amyloid precursor protein intracellular domain (in complex form). Our experimental findings indicate that the amyloid precursor protein intracellular domain is involved in the transcriptional regulation of learning- and memory-associated genes in hippocampal neurons. These data may provide new insights into the molecular mechanism underlying the symptoms of progressive memory loss in Alzheimer's disease. 展开更多
关键词 alzheimer's disease amyloid precursor protein amyloid precursor protein intracellular domain chromatin immunoprecipitation gene regulation chromatin DNA
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Correlation between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease
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作者 Hairong Qian Luning Wang +6 位作者 Xiaokun Qi Jianwei Liu Jing Liu Ling Ye Hengge Xie WeiWang Feng Qiu 《Neural Regeneration Research》 SCIE CAS CSCD 2009年第6期468-473,共6页
BACKGROUND: Studies addressing the correlation between prion protein gene codon 129 polymorphism, Alzheimer's disease, and cognitive disorders have mainly focused on Caucasians. However, prion protein gene codon 1... BACKGROUND: Studies addressing the correlation between prion protein gene codon 129 polymorphism, Alzheimer's disease, and cognitive disorders have mainly focused on Caucasians. However, prion protein gene codon 129 polymorphism is thought to also affect the Chinese Han and Wei populations. OBJECTIVE: To analyze the differences of prion protein gene codon 129 distribution among the elderly Chinese Han, East Asian, and Caucasian populations, and to study the correlation between prion protein gene codon 129 distribution and late-onset Alzheimer's disease. DESIGN, TIME AND SETTING: A gene polymorphism analysis was performed in the Institute of Geriatrics, General Hospital of Chinese PLA between January 2006 and January 2007. PARTICIPANTS: A total of 152 elderly Chinese Han people were selected from the Beijing Troop Cadre's Sanitarium. Among them, 60 patients with late-onset Alzheimer's disease, with a mean age of (82 ± 7) years (range 67-94 years) and disease course of (5.9 ± 4.4) years, comprising 44 males with a mean age of (83 ± 7) years and 16 females with a mean age of (78 ±7) years, were selected for the case group. An additional 92 healthy elderly subjects, with a mean of (76 ± 9) years (range 60-94 years), comprising 76 males with a mean age of (77 ± 9) years and 16 females with a mean age of (70 ± 8) years, were selected for the control group. There were no significant differences in age and gender between the two groups (P〉 0.05). METHODS: DNA was extracted from peripheral blood leukocytes using routine phenol/chloroform methodology. Prion protein gene codon 129 potymorphism and ApoE polymorphism were measured using PCR-restriction fragment length polymorphism. The ApoEε allele was considered the standard for analyzing correlations between prion protein gene codon 129 polymorphism and late-onset Alzheimer's disease. MAIN OUTCOME MEASURES: Prion protein gene codon 129 distribution; correlation between genotypic frequency and allele frequency of prion protein gene codon 129 with Alzheimer's disease; relationship between methionine/methionine genotype of priori protein gene, ApoEε4 allele, gender, and age of Alzheimer's disease patients. RESULTS: Methionine/methionine genotypic frequency of prion protein gene codon 129 was 94.08% in the Chinese elderly population, and the methionine/valine genotypic frequency was 5.92%. However, valine/valine homozygotes were not determined. There was no significant difference in prion protein gene codon 129 polymorphism between the Chinese elderly and East Asian populations (P〉 0.05). However, there was a significant difference between the Chinese elderly and the Caucasian population (P 〈 0.05). The methionine/methionine genotype for the positive and negative ApoEε4 alleles was a risk factor for increased incidence of Alzheimer's disease, but there was no significant difference between the positives and the negatives (odds ratio = 1.33, 95% confidence interval = 0.32-6.49, P〉 0.05). CONCLUSION: Prion protein gene codon 129 distribution in the Chinese elderly was different from the Caucasian population, which suggested that the methionine/methionine genotype of prion protein gene codon 129 negatively correlated with late-onset Alzheimer's disease. 展开更多
关键词 alzheimer's disease prion protein POLYMORPHISM
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Protein seeding in Alzheimer's disease and Parkinson's disease: Similarities and differences
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作者 Tarek Ibrahim JoAnne McLaurin 《World Journal of Neurology》 2014年第4期23-35,共13页
Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer's disease(AD) and Parkinson's disease(PD) have both demonstrated suscep... Neurodegenerative pathology can be seeded by introduction of misfolded proteins and peptides into the nervous system. Models of Alzheimer's disease(AD) and Parkinson's disease(PD) have both demonstrated susceptibility to this seeding mechanism, emphasizing the role of misfolded conformations of disease-specific proteins and peptides in disease progression. Thinking of the amyloidogenic amyloid-beta peptide(Aβ) and alpha-synuclein(α-syn), of AD and PD, respectively, as prionoids requires a comparison of these molecules and the mechanisms underlying the progression of disease. Aβ and α-syn, despite their size differences, are both natively unstructured and misfold into β-structured conformers. Additionally, several studies implicate the significant role of membrane interactions, such as those with lipid rafts in the plasma membrane, in mediating protein aggregation and transfer of Aβ and α-syn between cells that may be common to both AD and PD. Examination of inter-neuronal transfer of proteins/peptides provides evidence into the core mechanism of neuropathological propagation. Specifically, uptake of aggregates likely occurs by the endocytic pathway, possibly in response to their formation of membrane pores via a mechanism shared with pore-forming toxins. Failure of cellular clearance machinery to degrade misfolded proteins favours their release into the extracellular space, where they can be taken up by directly connected, nearby neurons. Although similarities between AD and PD are frequent and include mechanistically similar transfer processes, what differentiates these diseases, in terms of temporal and spatial patterns of propagation, may be in part due to the differing kinetics of protein misfolding. Several examples of animal models demonstrating seeding and propagation by exogenous treatment with Aβ and α-syn highlight the importance of both the environment in which these seeds are formed as well as the environment into which the seeds are propagated. Although these studies suggest potent seeding effects by both Aβ and α-syn, they emphasize the need for future studies to thoroughly characterize "seeds" as well as analyze changes in the nervous system in response to exogenous insults. 展开更多
关键词 alzheimer’s disease Parkinson’s disease Prionoid SEEDING Propagation protein MISFOLDING
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Humanin蛋白在Alzheimer’s病模型中神经保护作用的研究进展
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作者 李蓉 樊帅帅 +2 位作者 黄义方 王晓晖 王丽 《临床神经病学杂志》 CAS 2024年第4期297-300,共4页
研究表明,Humanin蛋白通过多种方式在抗Alzheimer’s病的过程中发挥神经保护作用。本综述从Humanin的发现、结构特征、神经保护的机制及其新型同源分泌肽Rattin的结构与功能方面介绍Humanin蛋白在Alzheimer’s病中神经保护作用的最新研... 研究表明,Humanin蛋白通过多种方式在抗Alzheimer’s病的过程中发挥神经保护作用。本综述从Humanin的发现、结构特征、神经保护的机制及其新型同源分泌肽Rattin的结构与功能方面介绍Humanin蛋白在Alzheimer’s病中神经保护作用的最新研究进展。 展开更多
关键词 alzheimer’s病 Β-淀粉样蛋白 HUMANIN Rattin
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Alzheimer’s disease:epidemiology,genetics,and beyond 被引量:5
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作者 王晓平 丁洪流 《Neuroscience Bulletin》 SCIE CAS CSCD 2008年第2期105-109,共5页
Alzheimer's disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially... Alzheimer's disease (AD) is an increasing epidemic threatening public health. Both men and women are susceptible to the disease although women are at a slightly higher risk. The prevalence of AD rises exponentially in elderly people from 1% at age of 65 to approximately 40%-50% by the age of 95. While the cause of the disease has not been fully understood, genetics plays a role in the onset of the disease. Mutations in three genes (APP, PSENI, and PSEN2) have been found to cause AD and APOE4 allele increases the risk of the disease. As human genomic research progresses, more genes have been identified and linked with AD. Genetic screening tests for persons at high risk of AD are currently available and may help them as well as their families better prepare for a later life with AD. 展开更多
关键词 alzheimer's disease amyloid precursor protein PRESENILIN APOE
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Insulin Resistance in Alzheimer's Disease and the Role of p53 Protein
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作者 Kazimierz Gasiorowski Barbara Brokos +1 位作者 Elzbieta Trypka Jerzy Leszek 《Journal of Pharmacy and Pharmacology》 2014年第6期327-335,共9页
Recent evidence reveals significant metabolic changes in AD (Alzheimer's disease), in which brain glucose utilization and energy production are impaired. The complex picture of metabolic disturbances in AD brains c... Recent evidence reveals significant metabolic changes in AD (Alzheimer's disease), in which brain glucose utilization and energy production are impaired. The complex picture of metabolic disturbances in AD brains could be explained by increase of p53 protein stabilization and activation in neurons exposed to diverse metabolic stress conditions. Activated p53 helps cells to adapt to various types of metabolic stresses. Chronic stress and long lasting p53 increase lead to inhibition of glucose uptake, downregulation of glycolysis, enhancement of lipid catabolism and fatty acid β-oxidation, also promote function of tricarboxylic acid cycle and force an oxidative phosphorylation. These effects are opposite to those of insulin, thus p53 activation leads to insulin resistance of cells. However, prolonged stress conditions unveil deleterious effects of p53-evoked insulin resistance in neurons; enhancement of transcription of pro-oxidant factors, accumulation of toxic rnetabolites (e.g., cerarnide, products of advanced glycation) and ROS (reactive oxygen species)---modified cellular components, together with activation of proapoptotic genes, could finally move a suicide death program of autophagy/apoptosis in neurons. The important role of p53 in driving insulin resistance in AD brains validates attempts to inhibit p53 activity in neurons since it could promise an improvement of the disease therapy. 展开更多
关键词 Insulin resistance p53 protein alzheimer's disease.
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Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases
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作者 Lifang Zhao Mingkai Zhang +4 位作者 Qimeng Li Xuemin Wang Jie Lu Ying Han Yanning Cai 《Neural Regeneration Research》 SCIE CAS 2025年第8期2373-2381,共9页
Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is k... Several promising plasma biomarker proteins,such as amyloid-β(Aβ),tau,neurofilament light chain,and glial fibrillary acidic protein,are widely used for the diagnosis of neurodegenerative diseases.However,little is known about the long-term stability of these biomarker proteins in plasma samples stored at-80°C.We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort.Plasma samples from 229 cognitively unimpaired individuals,encompassing healthy controls and those experiencing subjective cognitive decline,as well as 99 patients with cognitive impairment,comprising those with mild cognitive impairment and dementia,were acquired from the Sino Longitudinal Study on Cognitive Decline project.These samples were stored at-80°C for up to 6 years before being used in this study.Our results showed that plasma levels of Aβ42,Aβ40,neurofilament light chain,and glial fibrillary acidic protein were not significantly correlated with sample storage time.However,the level of total tau showed a negative correlation with sample storage time.Notably,in individuals without cognitive impairment,plasma levels of total protein and tau phosphorylated protein threonine 181(p-tau181)also showed a negative correlation with sample storage time.This was not observed in individuals with cognitive impairment.Consequently,we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time.Therefore,caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases,such as Alzheimer's disease.Furthermore,in cohort studies,it is important to consider the impact of storage time on the overall results. 展开更多
关键词 alzheimer’s disease amyloid-β diagnostic ability glial fibrillary acidic protein NEURODEGENERATION neurofilament light chain plasma biomarkers single molecule array storage time tau
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