Familial
Alzheimer disease-causing mutations in Presenilin 1 (PSEN1) are generally thought to shift the processing of APP toward longer, more amyloidogenic Aβ fragments. However, certain PSEN1 mutations cause severe reduction in gamma secretase function when expressed in the homozygous state, thus challenging the amyloid hypothesis. We sought to evaluate the effects of one such mutation, PSEN1 L435F, in more physiologic conditions and genetic contexts by using human induced pluripotent
stem cell (iPSC)-derived neurons from an individual with familial AD (fAD) linked to the PSEN1 L435F mutation, and compared the biochemical
phenotype of the iPS-derived neurons with
brain tissue obtained at autopsy from the same patient. Our results demonstrate that in the endogenous heterozygous state, the PSEN1 L435F
mutation causes a large increase in soluble Aβ43 but does not change the overall levels of soluble Aβ40 or Aβ42 when compared with control iPSC-neurons. Increased pathologically phosphorylated tau
species were also observed in PSEN1-mutant iPSC-neurons. Concordant changes in Aβ
species were present in autopsy
brain tissue from the same patient. Finally, the feasibility of using Aβ43
immunohistochemistry of
brain tissue to identify fAD cases was evaluated in a limited autopsy case series with the finding that strong Aβ43 staining occurred only in fAD cases.
Relevant Topics in Medical Sciences