The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble A[beta]43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue

Familial Alzheimer disease-causing mutations in Presenilin 1 (PSEN1) are generally thought to shift the processing of APP toward longer, more amyloidogenic A[beta] 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 A[beta]43 but does not change the overall levels of soluble A[beta]40 or A[beta]42 when compared with control iPSC-neurons. Increased pathologically phosphorylated tau species were also observed in PSEN1-mutant iPSC-neurons. Concordant changes in A[beta] species were present in autopsy brain tissue from the same patient. Finally, the feasibility of using A[beta]43 immunohistochemistry of brain tissue to identify fAD cases was evaluated in a limited autopsy case series with the finding that strong A[beta]43 staining occurred only in fAD cases. Key Words: [beta]-Amyloid, Alzheimer disease, iPSC, Presenilin, Stem cells, Tau.