A Novel A beta PP M722K Mutation Affects Amyloid-beta Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals
机构：[a]Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China神经内科首都医科大学宣武医院[b]Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China[c]Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China[d]Key Neurodegenerative Laboratory of Ministry of Education of the People’s Republic of China, Beijing, People’s Republic of China, Beijing, P.R. China
Background: Mutations within exons 16 and 17 of the amyloid-beta protein precursor (A beta PP) gene were the first known causes of early-onset familial Alzheimer's disease (EOFAD). Since the first A beta PP mutation was reported, 39 different A beta PP variations have been discovered in EOFAD. Objective: We described a novel A beta PP M722K mutation found in a Chinese familial Alzheimer's disease pedigree and confirmed its effects on amyloid-beta (A beta) secretion and tau phosphorylation. Methods: We performed direct sequencing of exons 16 and 17 of the A beta PP gene and coding exons 3-12 of the PSEN1 and PSEN2 genes for genetic analysis. N2a cells were transfected with wild-type A beta PP, A beta PP constructs harboring the M722K mutation, or A beta PP constructs harboring the Swedish mutation to demonstrate the effects of the A beta PP M722K mutation on A beta secretion and tau phosphorylation. Results: Different phenotypes of patients carrying the A beta PP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of A beta PP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of A beta(42) to A beta(40) without changes in sA beta PP alpha and sA beta PP beta. Tau phosphorylation at the AT8 sites was also increased. Conclusion: Maybe the A beta PP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased A beta(42)/A beta(40). Further studies should be conducted to validate the pathogenicity of A beta PP M722K and the interactions among gamma-secretase, APOE, and A beta PP.
基金：
the CHINA-CANADA Joint Initiative on Alzheimer’s Disease and Related Disorders (81261120571),
Key Medical Professional Development Plan of Beijing Municipal Administration of Hospitals (ZY201301),
Seed Grant of International Alliance of Translational Neuroscience (PXM2014 014226 000006),
the National Science and Technology Major Projects for “Major New Drug Innovation and Development” of the Twelfth 5-year Plan Period (2011ZX09307-001-03),
the National Key Technology R&D Program in the Eleventh Five-year Plan Period (2006BAI02B01),
the Key Project of the National Natural Science Foundation of China (30830045),
the Scientific Promoting Project of the Beijing Institute for Brain Disorders (BIBDPXM2014 014226 000016).
第一作者机构：[a]Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China
通讯作者：
通讯机构：[*1]Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing 100053, P.R. China.
推荐引用方式(GB/T 7714)：
Qianqian Wang,Jianping Jia,Wei Qin,et al.A Novel A beta PP M722K Mutation Affects Amyloid-beta Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals[J].JOURNAL OF ALZHEIMERS DISEASE.2015,47(1):157-165.doi:10.3233/JAD-143231.
APA：
Qianqian Wang,Jianping Jia,Wei Qin,Liyong Wu,Dan Li...&Hanzhi Li.(2015).A Novel A beta PP M722K Mutation Affects Amyloid-beta Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals.JOURNAL OF ALZHEIMERS DISEASE,47,(1)
MLA：
Qianqian Wang,et al."A Novel A beta PP M722K Mutation Affects Amyloid-beta Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals".JOURNAL OF ALZHEIMERS DISEASE 47..1(2015):157-165
