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.
Conclusion: 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.
