Familial Alzheimer's disease mutations in amyloid precursor protein impair calcineurin signaling to NMDA receptors.

ABSTRACT: Familial Alzheimer's disease (FAD) is frequently associated with mutations in the amyloid precursor protein (APP), which are thought to lead to cognitive deficits by impairing NMDA receptor (NMDAR)-dependent forms of synaptic plasticity. Given the reliance of synaptic plasticity on NMDAR-mediated Ca²⁺ entry, shaping of NMDAR activity by APP and/or its disease-causing variants could provide a basis for understanding synaptic plasticity impairments associated with FAD. A region of APP (residues 639-644 within APP695) processed by the γ-secretase complex, which generates amyloid-β peptides, is a hotspot for FAD mutations. This region bears similarity to a binding motif for calcineurin (CaN), a Ca²⁺/calmodulin-dependent phosphatase. Interaction assays confirm that APP ass

SUBMITTER: Tavalin SJ 

PROVIDER: S-EPMC11910330 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature