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phosphorylated tau as a toxic agent in synaptic mitochondria: implications in aging and Alzheimer’s disease

Neural Regeneration Research 2022年第8期17卷 1645-1651页

作者： Angie K.Torres Bastián I.Rivera Catalina M.Polanco Claudia Jara Cheril Tapia-Rojas Laboratory of Neurobiology of Aging Centro de Biología Celular y Biomedicina(CEBICEM)Facultad de Medicina y CienciaUniversidad San SebastiánSede Los LeonesSantiagoChile

During normal aging,there is a decline in all physiological functions in the *** of the most affected organs is the brain,where neurons lose their proper synaptic function leading to cognitive *** is one of the main risk factors for the development of neurodegenerative diseases,such as Alzheimer’s *** of the main responsible factors for synaptic dysfunction in aging and neurodegenerative diseases is the accumulation of abnormal proteins forming *** most studied brain aggregates are the senile plaques,formed by Aβpeptide;however,the aggregates formed by phosphorylated tau protein have gained relevance in the last years by their *** is reported that neurons undergo severe mitochondrial dysfunction with age,with a decrease in adenosine 5′-triphosphate production,loss of the mitochondrial membrane potential,redox imbalance,impaired mitophagy,and loss of calcium buffer ***,abnormal tau protein interacts with several mitochondrial proteins,suggesting that it could induce mitochondrial ***,whether tau-mediated mitochondrial dysfunction occurs indirectly or directly is still unknown.A recent study of our laboratory shows that phosphorylated tau at Ser396/404(known as PHF-1),an epitope commonly related to pathology,accumulates inside mitochondria during normal *** accumulation occurs preferentially in synaptic mitochondria,which suggests that it may contribute to the synaptic failure and cognitive impairment seen in aged ***,we review the main tau modifications promoting mitochondrial dysfunction,and the possible mechanism ***,we discuss the evidence that supports the possibility that phosphorylated tau accumulation in synaptic mitochondria promotes synaptic and cognitive impairment in ***,we show evidence and argue about the presence of phosphorylated tau PHF-1 inside mitochondria in Alzheimer’s disease,which could be considered as an early event

关键词： age pathology aging Alzheimer’s disease hippocampus memory mitochondria PHF-1 phosphorylated tau synaptic mitochondria tau

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Specific serum antibody binding to phosphorylated and non-phosphorylated tau in non-cognitively impaired,mildly cognitively impaired,and Alzheimer’s disease subjects:an exploratory study

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Translational Neurodegeneration 2017年第1期6卷 324-332页

作者： Andrea C.Klaver Mary P.Coffey David A.Bennett David A.Loeffler Department of Neurology Beaumont Research InstituteBeaumont HealthRoyal OakMIUSA Department of Biostatistics Beaumont Research InstituteBeaumont HealthRoyal OakMIUSA Rush Alzheimer’s Disease Center ChicagoIL 60612USA

Background:tau vaccination and administration of anti-tau antibodies can prevent pathology and cognitive impairment in transgenic mouse models of tauopathy,suggesting that therapies which increase anti-tau antibodies might slow the development and/or progression of Alzheimer’s disease(AD).The extent to which individuals with no cognitive impairment(NCI)possess serum anti-tau antibodies,and whether their concentrations of these antibodies differ from anti-tau antibody levels in persons with mild cognitive impairment(MCI)or AD,are *** studies measuring these antibodies did not account for antibody polyvalent binding,which can be extensive,nor that antibody binding to phosphorylated tau peptides could be due to binding to non-phosphorylated epitopes on those ***:An ELISA controlling for these factors was used to measure the specific binding of serum IgG and IgM to phosphorylated(“ptau;”phosphorylated at Serine-199 and Serine-202)and non-phosphorylated(“non-ptau”)tau 196-207 in subjects with NCI,MCI,or AD(n=10/group).Between-group differences in these antibody levels were evaluated for statistical significance,and correlations were examined in pooled data from all subjects between these antibody levels and subject age,global cognitive functioning,and NFT ***:Specific IgG binding to ptau and non-ptau was detected in all subjects except for one NCI *** IgM binding was detected to ptau in all subjects except for two AD patients,and to non-ptau in all *** ptau IgG was increased in MCI subjects by 53% and 70% *** and NCI subjects respectively(both ptau IgG(p=0.052),ptau IgM,or non-ptau ***-ptau IgG was negatively associated with global cognition(Spearman rho=−0.50).Conclusions:Specific binding of serum IgG and IgM to phosphorylated and non-phosphorylated tau may be present in older persons regardless of their cognitive *** IgG

关键词： Alzheimer’s disease Antibodies Elisa ELISA Mild cognitive impairment phosphorylated tau

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cPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus

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Neuroscience Bulletin 2022年第10期38卷 1153-1169页

作者： Jiayin Zheng Yue Wang Yue Liu Song Han Ying Zhang Yanlin Luo Yi Yan Junfa Li Li Zhao Department of Neurobiology and Center of Stroke Beijing Institute for Brain DisordersCapital Medical UniversityBeijing100069China The National Clinical Research Center for Mental Disorders&Beijing Key Laboratory of Mental Disorders Beijing Anding HospitalCapital Medical UniversityBeijing100088China Advanced Innovation Center for Human Brain Protection Capital Medical UniversityBeijing100088China

Type 1 diabetes mellitus(T1DM)-induced cognitive dysfunction is common,but its underlying mechanisms are still poorly *** this study,we found that knockout of conventional protein kinase C(cPKC)γsignificantly increased the phosphorylation of tau at Ser214 and neurofibrillary tangles,but did not affect the activities of GSK-3βand PP2A in the hippocampal neurons of T1DM ***γdeficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM *** of autophagy greatly alleviated the cognitive impairment induced by cPKCγdeficiency in T1DM ***,cPKCγdeficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in *** high glucose-induced tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR *** conclusion,these results indicated that cPKCγpromotes autophagy through the AMPK/mTOR signaling pathway,thus reducing the level of phosphorylated tau at Ser214 and neurofibrillary tangles.

关键词： Conventional protein kinase C(cPKC)γ tau phosphorylated tau Autophagy AMPK/mTOR signaling pathway

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散发性早发阿尔茨海默病中磷酸化tau蛋白的高负荷和特异性楔前叶萎缩:一项前瞻性队列研究

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Science Bulletin 2023年第22期68卷 2817-2826,M0006页

作者：吕心怡程昭昭王琼高峰戴林斌杜琛刘畅谢强申勇施炯 Department of Neurology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Neurodegenerative Disorder Research Center Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Radiology The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Department of Nuclear Medicine The First Affiliated Hospital of USTCDivision of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefei 230001China Anhui Province Key Laboratory of Biomedical Aging Research University of Science and Technology of ChinaHefei 230001China

早发性阿尔茨海默病(EOAD)是阿尔茨海默病(AD)的罕见且严重的亚型,于65岁之前发病,占所有AD病例的5%~10%.以往关于EOAD的研究主要集中在家族性遗传人群,而对于占EOAD病例85%~90%的散发性EOAD(sEOAD)的研究则较为有限.在这项前瞻性队列... 详细信息

早发性阿尔茨海默病(EOAD)是阿尔茨海默病(AD)的罕见且严重的亚型,于65岁之前发病,占所有AD病例的5%~10%.以往关于EOAD的研究主要集中在家族性遗传人群,而对于占EOAD病例85%~90%的散发性EOAD(sEOAD)的研究则较为有限.在这项前瞻性队列研究中,共纳入sEOAD110例,晚发性AD(LOAD)89例,年龄匹配对照组75例.研究对象排除了家族性EOAD患者,所有纳入AD患者均符合基于ATN框架下的生物标志物证据的诊断标准.对纳入患者进行了患病危险因素分析、多维度认知功能评估、多模态分子影像学评估及脑脊液/外周血生物标记物检测.结果显示,与LOAD患者相比,sEOAD患者没有表现出特定的危险因素,但表现出更严重的执行功能损害和双侧楔前叶萎缩.在sEOAD患者中的脑脊液和血浆中磷酸化tau181(P-tau181)水平较LOAD组显著升高.本研究探讨了散发性EOAD人群的临床特征,发现了tau蛋白磷酸化在sEOAD发生和进展中的重要性,有助于全面了解AD的病因、发病年龄决定因素和疾病进展,并为潜在的治疗策略提供了重要思路.

关键词： Alzheimer’s disease Early-onset Alzheimer’s disease Familial hereditary phosphorylated tau Precuneus

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Ligustrazine Attenuates Hyperhomocysteinemia-induced Alzheimer-like Pathologies in Rats

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Current Medical Science 2021年第3期41卷 548-554页

作者： Qing ZHANG Jing WANG Liang ZHU Shi-jie JIANG Juan LIU Lin-xiao WANG Xi-hu QIN Laboratory of Neurological Diseases the Afiliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChangzhou 213003China Department of Pediatrics the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChangzhou 213003China Department of Anesthesiology the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChanghow 213003China Department of Orthopedics the Affliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChangehou 213003China Department of Endocrinology the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChangzhou 213003China Department of General Surgery the Affiliated Changzhou No.2 People's Hospital of Nanjing Medical UniversityChangzhou 213000China

Ligustrazine,an alkaloid extracted from the traditional Chinese herbal medicine Ligusticum Chuanxiong Hort,has been clinically applied to treat the cerebrovascular ***(Hhcy)is an independent risk factor for Alzheimer's disease(AD).Memory deficits can be caused by Hhcy via pathologies of Aβ-like tau and amyloid-β(Aβ)in the ***,we investigated whether homocysteine(Hey)can induce Aβ-like pathologies and the effects of ligustrazine on these *** Hey rat model was constructed by 14-day Hey injection via vena caudalis,and rats were treated with daily intragastric administration of ligustrazine at the same *** found that the pathologies of tau and Aβ were induced by Hey in the hippocampus,while the Hcy-induced tau hyperphosphorylation and Aβ accumulation could be markedly attenuated by simultaneous ligustrazine *** data demonstrate that ligustrazine may be used as a promising neuroprotective agent to treat the Hcy-induced Aβ-like pathologies.

关键词： Alzheimer's disease ligustrazine hyperhomocysteinemia phosphorylated tau cognitive impairment

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Development of an Ultrasensitive ELISA-Bienzyme Colorimetric Substrate Recycle Assay for Measurement of tau

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Wuhan University Journal of Natural Sciences 2005年第6期10卷 1047-1050页

作者： DUAN Qiu-hong WANG Xiao-chuan WANG Xi-ming ZHOU Xin-wen HE Shan-shu WANG Jian-zhit Department of Biochemistry Tongji Medical College Huazhong University of Science and Technology Wuhan 430030 Hubei China

On the basis of convemional enzyme-linked immunosorbent assay （ELISA） and bienzyme suhstrate recycle, ELISA-bienzyme colorimetric substrate recycle was developed in the present study. The sensitivity of this method increased 15 times than that of ELISA for the measurement of tau and increased 55 times for p-tau. The linear detective rang of this method expanded 3 times higher than that of conventional *** for tau and had the san;e as *** for ***, ***-bienzyme colorimetric substrate recycle could be used to detect abnormally phosphorylated tau in cerehrospinal fluid.

关键词： ELISA-bienzyme colorimetric substrate recycle tau phosphorylated tau

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mTOR signaling play a key role in tau phosphorylation in SAMP8 mice

mTOR signaling play a key role in Tau phosphorylation in SAM...

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中国神经科学学会第九届全国学术会议暨第五次会员代表大会

作者： Yuan GENG~(1,2),Qin-Ying MA~(1,2),Jing QIANG~(1,2),Ping GU~(1,2),Yan-Yong WANG~(1,2),Ming-Wei WANG~(*,1,2) 1 Department of Neurology,the Frist Hospital of Hebei Medical University,Shijiazhuang 050031,China 2 Brain Aging and Cognitive Neuroscience Laboratory of Hebei,Shijiazhuang 050031,China

＜正＞Objective The mammalian target of rapamycin（mTOR） kinase is an inhibitor of macroautophagy, which is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in *** evidence suggested that chronic increase in mTOR function occurring during aging may promote the development of tau *** senescence accelerated mouse prone 8（SAMP8） is a mice strain widely used as a rodent model of aging and senile *** present study aimed to explore whether mTOR signaling pathway has effect in the neurodegenerative changes of SAMP8 mice and whether rapamycin administration could alleviate the neurodegenerative *** The primary neurons were obtained from the hippocampus of newborn SAMP8 and SAMRl mice,and at the seventh day of culture,0.5 or 1.0μM rapamycin was added into the culture medium,and at the tenth day,neurons were observed after immunofluorenscence *** levels of phosphorylated p70S6K,phosphorylated mTOR,tau[pS199]and tau[pS396]were detected with Western blot. Results In SAMP8 hippocampal neurons,the levels of phosphorylated p70S6K at Thr389 and mTOR（pSer2448） were significantly higher than in the control *** activity signaling was upregulated in the neurons of SAMP8 at the tenth *** neurons extracted from SAMP8 were in a poor state in contrast to the SAMPR1,most processes broken and presented "bead-like" *** administration significantly reduced the levels of phosphorylated p70S6K at Thr389 in SAMP8 contrast to SAMRl in both treated *** treated with 0.5 uM rapamycin for 3 d,a mTOR inhibitor,the neurons from SAMP8 seems better than non-treated group,part of processes were smooth and slender,although part of neurons almost all processes broken and *** presentation of tau [pS199]and tau[pS396]both decreased significantly contrast to the control *** treated with 1.0 uM rapamycin,cell state was worse than the untreated group,most neurons we

关键词： senescence accelerated mouse prone 8 mTOR signaling phosphorylated tau rapamycin

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