Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction, progression, and prion-like spread of Alzheimer’s disease pathogenesis

The hippocampus is a primary region affected in Alzheimer’s disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis in patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Notably, proteomic analysis of the graft enabled the identification of proteomic alterations in AD patient brain cells, associated with increased levels of β-sheet structures and Aβ42 peptides. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of disease progression from early to end stage AD. Our data showcase patient-based models to study the cellular origin, progression, and prion-like spread of AD pathogenesis.Highlights-AD patient iPSC-derived brain cells survive in the hippocampus of immunodeficient mice 6 months post-transplantation.-Proteomic analysis of the grafts reveals profound alterations in cellular biological pathways in iPSC-derived hippocampal cells despite absence of senile plaques.-Proteomic alterations within transplanted AD iPSC-derived hippocampal cells are reminiscent of early/prodromal AD.-AD-grafted cells induce proteomic changes in host mouse cells.