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Mutant amyloid precursor protein and presenilin-1 genes effect on ischemia vulnerability via calcium homeostasis disturbance

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Neural Regeneration Research 2009年第12期4卷 1049-1054页

作者： Liangyu Zou Xiaofan Chu Haiyan Yin Xuejun Fu Yiguang Rao Gang Li Yi Lu Department of Neurology Shenzhen People's Hospital Second Clinical College Jinan University Shenzhen 518020 Guangdong Province China Intensive Care Unit Guangzhou Red Cross Hospital Fourth Affiliated Hospital Jinan University Guangzhou 510250 Guangdong Province China

BACKGROUND： Previous studies have demonstrated that mutant amyloid precursor protein （APP） or presenilin-1 （PS1） genes increase susceptibility to ischemic brain damage induced by middle cerebral artery occlusion. Possible mechanisms include over-production of beta-amyloid peptide （Aβ）. OBJECTIVE： Because Aβ is over-produced in the APP/PS1 double-transgenic mouse, the present study focused on mechanisms of increased ischemic damage due to mutant APP and PS1 genes by measuring oxidative stress, mitochondrial function, and calcium homeostasis. DESIGN, TIME AND SETTING： The non-randomized, controlled, in vivo and in vitro experiments were performed at the Medical Research Center, Second Clinical College, Jinan University between May and October 2008. MATERIALS： Male APP transgenic mice carrying the mutant 695swe gene and female PS1 transgenic mice carrying the mutant Leu235Pro gene were donated from the University of Hong Kong. SHSY5Y human neureblastoma cells were purchased from ATCC （Manassas, VA, USA）, and Aβ1-42 was obtained from Sigma-Aldrich （St. Louis, MO, USA）. METHODS： APP transgenic mice were mated with PS1 transgenic mice to produce APP/PS1 double-transgenic mice and wildtype littermates mice. The photothrombotic stroke model was induced in six APP/PS1 double-transgenic and 6 wildtype littermates mice. SHSY5Y human neuroblastoma cells were cultured in vitro, and were divided into 4 groups： Aβ group, cells were exposed to 5 pmol/L Aβ for 24 hours; oxygen-glucose deprivation （OGD） group, cells were exposed to OGD for 1 hour after treatment with sterile, ultra-pure water for 24 hours; OGD＋Aβ group, cells were exposed to OGD and Aβfor 1 hour after treatment with 5 pmol/L Aβ for 24 hours; sham control group： cells were exposed to sterile, ultra-pure water for 25 hours. OGD was achieved by exposing the cells to glucose-free DMEM and placing the cells in an anaerobic chamber flushed with 5% CO2 and 95% N2 （v/v） at 37 ℃ for 1 hour. MAIN OUTCOME MEASURES： TTC staining

关键词： amyloid precursor protein presenilin-1 cerebral ischemia calcium d

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Efficacy of Sailuotong(塞络通)on neurovascular unit in amyloid precursor protein/presenilin-1 transgenic mice with Alzheimer's disease

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Journal of Traditional Chinese Medicine 2024年第2期44卷 289-302页

作者： SUN Linjuan LI Chengfu LIU Jiangang LI Nannan HAN Fuhua QIAO Dandan TAO Zhuang ZHAN Min CHEN Wenjie ZHANG Xiaohui TONG Chenguang CHEN Dong Qi Jiangxia LIU Yang LIANG Xiao ZHENG Xiaoying ZHANG Yunling Department of Neurology Xiyuan HospitalChina Academy of Chinese Medical SciencesBeijing 100091China China Population and Development Research Center Beijing 100081China Department of Institute of Population Research Peking UniversityBeijing 100087China Graduate School of China Academy of Chinese Medical Sciences Beijing 100700China Graduate School of Beijing University of Chinese Medicine Beijing 100029China

OBJECTIVE:To discuss the influence of Sailuotong(塞络通,SLT)on the Neurovascular Unit(NVUs)of amyloid precursor protein(APP)/presenilin-1(PS1)mice and evaluate the role of gas supplementation in activating blood circulation during the progression of Alzheimer's disease(AD).METHODS:The mice were allocated into the following nine groups:(a)the C57 Black(C57BL)sham-operated group(control group),(b)ischaemic treatment in C57BL mice(the C57 ischaemic group),(c)the APP/PS1 sham surgery group(APP/PS1 model group),(d)ischaemic treatment in APP/PS1 mice(APP/PS1 ischaemic group),(e)C57BL mice treated with aspirin following ischaemic treatment(C57BL ischaemic+aspirin group),(f)C57BL mice treated with SLT following ischaemic treatment(C57BL ischaemic+SLT group),(g)APP/PS1 mice treated with SLT(APP/PS1+SLT group),(h)APP/PS1 mice treated with donepezil hydrochloride following ischaemic treatment(APP/PS1 ischaemic+donepezil hydrochloride group)and(i)APP/PS1 mice treated with SLT following ischaemic treatment(APP/PS1 ischaemic+SLT group).The ischaemic model was established by operating on the bilateral common carotid arteries and creating a *** Morris water maze and step-down tests were used to detect the spatial behaviour and memory ability of *** hippocampus of each mouse was observed by haematoxylin and eosin(HE)and Congo red *** ultrastructure of NVUs in each group was observed by electron microscopy,and various biochemical indicators were detected by enzymelinked immunosorbent assay(ELISA).The protein expression level was detected by Western *** mRNA expression was detected by quantitative real-time polymerase chain reaction(qRT-PCR).RESULTS:The results of the Morris water maze and step-down tests showed that ischemia reduced learning and memory in the mice,which were restored by *** results of HE staining showed that SLT restored the pathological changes of the *** Congo red staining results revealed that SLT also improved the scattered

关键词： Alzheimer disease amyloid beta-protein precursor presenilin-1 mice transgenic replenishing Qi and activating blood neurovascular unit Sailuotong

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presenilin-1 Regulates Capacitative Calcium Entry Through The γ-secretase

Presenilin-1 Regulates Capacitative Calcium Entry Through Th...

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中国生理学会第24届全国会员代表大会暨生理学学术大会

作者：唐俊傑張敬浩香港大學生理學系香港大學深圳研究院

γ-secretase is a multimeric intramembrane protease which responsible for the cleavage of various type-I transmembrane *** proteolytic activity has played an important role in the Familial Alzheimer’s disease（FAD）pathogenesis as the amyloid plaque,a pathogenic hallmark of AD,was resulted from the abnormal processing of Amyloid precursor protein（APP）byγ-*** amyloidogenic amyloid precipitation in FAD is caused by the mutation in presenilin-1（PS1）which enhanced the proteolytic activity while loosen its substrate specificity,leading to the production of insoluble Aβ*** from the formation of amyloid plaques,FAD-linked PS1 mutations can also disrupt cellular calcium homeostasis by attenuating Ca2+entry through the capacitative Ca2+entry（CCE）***,whether and how the CCE deficits related to alteredγ-secretase activity was *** human neuroblastoma SH-SY5Y and Ca2+imaging technique,we demonstrated that the attenuation of CCE wasγ-secretase *** cell withγ-secretase inhibitor,DAPT,restored the CCE *** homology search,we found that the transmembrane region of Stromal interaction molecule 1（STIM1,one of the key molecular player of CCE）,was similar to those of APP,suggesting that STIM1 could be a substrate ofγ-*** further investigate thisγ-secretase mediated cleavage,fluorogenic peptide cleavage assay was employed and the result demonstrated that STIM1 was cleavable byγ-*** summary,we hypothesized that STIM1 is functionally impaired by FAD-linked PS1 mutation through the proteolytic cleavage byγ-secretase,leading to the attenuation of *** identification of STIM1 as a substrate forγ-secretase provides insights into the pathogenic mechanism of AD,and sheds the light for the development of therapeutic agent to treat the disease.

关键词： Alzheimer’s Disease presenilin-1 Capacitative Calcium Entry

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Down-regulation amyloid β-protein 42 production by interfering with transcript of presenilin 1 gene with siRNA

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Acta Pharmacologica Sinica 2004年第12期25卷 47-52页

作者： Huan-min LUO2, Hui DENG, Fei XIAO, Qin GAO, Wen WENG, Pei-fen ZHANG, Xiao-guang LI Neuropharmacological Research Laboratory, College ofPharmacy, Ji-nan University, Guangzhou 510632, China Neuropharmacological Research Laboratory College of Pharmacy Ji-nan University Guangzhou 510632 Chin

AIM: To investigate the pathogenesis of Aβ42yielding and new drug targets as well as the possibility of RNA interference (RNAi) technique for treatment of Alzheimer disease (AD). METHODS: Human AD presenilin 1 (PS1) cDNA sequence was obtained from NCBI website. The three sites of RNAi action and one missense control site were selected in PS1 cDNA through online design of Ambion company. To confirm specificity of these sites, we conducted a BLAST search of the IMAGE EST library. The corresponding double-stranded DNA was used to construct pSilencer 3.1-H1 plasmid, which could transcribe small interference RNA (siRNA). Then, the pSliencer 3.1-H1 plasmids were transfected into CHO/PS1/APP cells with SuperFect transfection reagent. The cells have been transfected with the mutant PS1 and APP gene of AD. All the CHO/PS1/APP cells with pSliencer 3.1-H1 plasmids were screened out using G418. Transcripts of PS1 gene in CHO/PS1/APP were measured by RT-PCR, the contents of PS1 peptide and Aβ42 production inside CHO/PS1/APP cells were examined through Western blot and the Aβ42 change of secretion by CHO/PS1/APP was determined with ELISA. RESULTS: The site 3 of PS1 mRNA was inhibited by RNAi after 2 d. The effect was more obvious with the time. The peptide corresponding to PS1 gene and Aβ42 production in CHO/PS1/APP cells were both reduced after siRNA interfere for 3 d. Aβ42 secretion by CHO/PS1/APP cells began to reduce on d 3, and reached the most significance on d 5. There was a time-dependent relationship between the transcript of PS1 gene and the production of Aβ42with RNAi action. CONCLUSION: PS1 is essential for γ-secretase activity. Inhibition of the PS1 can decrease the levels of Aβ42. Some sites of PS1 mRNA, for example, the site 3, may serve as a new drug target and RNAi probably can be used for treatment of AD.

关键词： amyloid beta-protein amyloid beta-protein precursor secretase presenilin-1 RNA interference small-interfering RNA Alzheimer disease

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与presenilin-1相关的早发型阿尔茨海默病家系临床及遗传学研究

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中华老年医学杂志 2021年第6期40卷 727-732页

作者：陆素洁高媛妍徐晨曦汤荟冬曹立民航上海医院上海交通大学医学院附属瑞金医院古北分院神经内科 200336 上海交通大学医学院附属瑞金医院神经内科 200025

目的探讨早发型阿尔茨海默病(EOAD)先证者及其家系的临床与遗传学特点和致病基因突变特征。方法︰对3例EOAD先证者及其家庭成员进行分析并总结临床特点。对3例先证者及其亲属采集外周血,运用二代测序(NGS)方法进行基因检测,通过外显子... 详细信息

目的探讨早发型阿尔茨海默病(EOAD)先证者及其家系的临床与遗传学特点和致病基因突变特征。方法︰对3例EOAD先证者及其家庭成员进行分析并总结临床特点。对3例先证者及其亲属采集外周血,运用二代测序(NGS)方法进行基因检测,通过外显子捕获测序发现先证者携带的致病突变,进一步通过Sanger测序对先证者及其家属的该基因位点进行验证。进一步探讨EOAD的临床及遗传学特点。结果第一例为家族性EOAD,基因突变类型为presenilin-1(PSEN1)基因8号外显子存在的c.851C>T(p.P284L)杂合突变。第二例也为家族性EOAD,基因突变类型为PSEN1基因第6号外显子的c.497_499del(***167del)杂合缺失突变。第三例先证者无家族史,受检者样本中发现PSEN1基因7号外显子上存在c.C626C>A(G209E)杂合突变。3例患者均以记忆力下降为首发症状,伴随的临床表现有行动迟缓、步态异常、言语不清、大小便失禁﹑精神症状等。结论﹑丰富了EOAD患者的突变类型及EOAD患者的临床表现,总结该基因与EOAD的遗传学特点可以增加对该病发病机制的认知,并为遗传分类和临床诊断提供帮助。

关键词：阿尔茨海默病 presenilin-1 遗传学

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Effects of presenilins and β-amyloid precursor protein on delayed rectifier potassium channels in cultured rat hippocampal neurons

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Acta Pharmacologica Sinica 2004年第2期25卷 55-59页

作者： Wei ZHANG, Hong-wei JIN, Xiao-liang WANG2 Department of Pharmacology, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100050, China Department of Pharmacology Institute of Materia Medica Peking Union Medical College and Chinese Academy of Medical Science Beijing 100050 China Wyatt Technology Corporation 6300 Hollister Avenue Santa Barbara CA 93117-3253

AIM: To study the effects of presenilin-1 (PS-1), presenilin-2 (PS-2), and amyloid beta-protein precursor (APP695) on delayed rectifier potassium channels (IK) in the cultured rat hippocampal neurons. METHODS: PS-1, PS-2, and APP695 were transfected into the cultured rat hippocampal neurons by transient transfection techniques. The IK current was observed by the whole cell patch-clamp techniques. RESULTS: IK was increased in cultured rat hippocampal neurons, after transient transfection of PS-1, PS-2, and APP695. IK amplitudes and densities were significantly increased from (1689±412) pA, (48±18) pA/pF (mock cells, GFP alone, n=17) to (5565±1403) pA, (252±107) pA/pF (PS-1/GFP, n=22, P0.05). CONCLUSION: Overexpression of PS-1, PS-2, and APP695 increased IK in the cultured rat hippocampal neurons. The upregulation of IK may be related to neuronal apoptosis after PS-1, PS-2, and APP695 were transfected.

关键词： presenilin-1 presenilin-2 amyloid beta-protein precursor potassium channels transfection patch- clamp techniques

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Degenerative alterations in noradrenergic neurons of the locus coeruleus in Alzheimer's disease

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Neural Regeneration Research 2013年第24期8卷 2249-2255页

作者： Lihua Liu Saiping Luo Leping Zeng Weihong Wang Liming Yuan Xiaohong Jian Department of Histology & Embryology School of Basic Medical Sciences Central South University Department of Nursing Medical College of Hunan Normal University Third Department of Surgery Agricultural Division Four Hospital Xinjiang Production and Construction Corps Department of Anatomy & Neurobiology School of Basic Medical Sciences Central South University Department of Anatomy Medical College of Hunan Normal University

Mice carrying mutant amyloid precursor protein and presenilin-1 genes （APP/PS1 double trans- genic mice） have frequently been used in studies of Alzheimer＇s disease; however, such studies have focused mainly on hippocampal and cortical changes. The severity of Alzheimer＇s disease is known to correlate with the amount of amyloid-13 protein deposition and the number of dead neurons in the locus coeruleus. In the present study, we assigned APP/PS1 double transgenic mice to two groups according to age： young mice （5-6 months old） and aged mice （16-17 months old）. Age-matched wild-type mice were used as controls. Immunohistochemistry for tyrosine hydroxylase （a marker of catecholaminergic neurons in the locus coeruleus） revealed that APP/PS1 mice had 23% fewer cells in the locus coeruleus compared with aged wild-type mice. APP/PS1 mice also had increased numbers of cell bodies of neurons positive for tyrosine hydroxylase, but fewer tyrosine hydroxylase-positive fibers, which were also short, thick and broken. Quantitative analysis using unbiased stereology showed a significant age-related increase in the mean volume of tyrosine hy- droxylase-positive neurons in aged APP/PS1 mice compared with young APP/PS1 mice. Moreover, the mean volume of tyrosine hydroxylase-positive neurons was positively correlated with the total volume of the locus coeruleus. These findings indicate that noradrenergic neurons and fibers in the locus coeruleus are predisposed to degenerative alterations in APP/PS1 double transgenic mice.

关键词： neural regeneration presenilin-1 Alzheimer's disease tyrosine hydroxylase locus coeruleus noradrenergic neuron ^-amyloid senile plaques grants-supported paper neuroregeneration

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