title: A Novel AβPP M722K Mutation Affects Amyloid-β Secretion and Tau Phosphorylation and May Cause Early-Onset Familial Alzheimer's Disease in Chinese Individuals.
abstract: BACKGROUND
  Mutations within exons 16 and 17 of the amyloid-β protein precursor (AβPP) gene were the first known causes of early-onset familial Alzheimer's disease (EOFAD). Since the first AβPP mutation was reported, 39 different AβPP variations have been discovered in EOFAD.
  
  
  OBJECTIVE
  We described a novel AβPP M722K mutation found in a Chinese familial Alzheimer's disease pedigree and confirmed its effects on amyloid-β (Aβ) secretion and tau phosphorylation.
  
  
  METHODS
  We performed direct sequencing of exons 16 and 17 of the AβPP gene and coding exons 3-12 of the PSEN1 and PSEN2 genes for genetic analysis. N2a cells were transfected with wild-type AβPP, AβPP constructs harboring the M722K mutation, or AβPP constructs harboring the Swedish mutation to demonstrate the effects of the AβPP M722K mutation on Aβ secretion and tau phosphorylation.
  
  
  RESULTS
  Different phenotypes of patients carrying the AβPP M722K mutation maybe were related to different apolipoprotein E genotypes. The expression of AβPP M722K in mouse neuroblastoma N2a cells induced a 1.7-fold increased ratio of Aβ 42 to Aβ 40 without changes in sAβPPα and sAβPPβ. Tau phosphorylation at the AT8 sites was also increased.
  
  
  CONCLUSIONS
  Maybe the AβPP M722K mutation contributed to the cause of EOFAD in this Chinese pedigree mediated by increased Aβ 42/Aβ 40. Further studies should be conducted to validate the pathogenicity of AβPP M722K and the interactions among γ-secretase, APOE, and AβPP.
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, People's Republic of China, Beijing, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Jia
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, People's Republic of China, Beijing, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Qin
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, People's Republic of China, Beijing, P.R. China.
authors.forename: Liyong
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, People's Republic of China, Beijing, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.|Center of Alzheimer's Disease, Beijing Institute for Brain Disorders, Beijing, P.R. China.|Beijing Key Laboratory of Geriatric Cognitive Disorders, Beijing, P.R. China.|Key Neurodegenerative Laboratory of Ministry of Education of the People's Republic of China, Beijing, People's Republic of China, Beijing, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Neurology, Xuan Wu Hospital, Capital Medical University, Beijing, P.R. China.
authors.forename: Hanzhi
authors.initials: H
authors.lastname: Li
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics; D045744:Cell Line, Tumor; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008239:Lysine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D051379:Mice; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation / Q000235:genetics; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; D008715:Methionine; D008239:Lysine
keywords: Aβ42/Aβ40; AβPP M722K mutation; amyloid-β protein precursor; familial Alzheimer’s disease; tau phosphorylation