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

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 associates with CaN in native tissue as well as in a heterologous expression system. This capacity to bind CaN extends to APP family members amyloid precursor-like protein 1 and amyloid precursor-like protein 2 (APLP1 and APLP2, respectively). Electrophysiological analysis demonstrates that APP and its family members limit NMDAR activity, in a manner consistent with CaN-dependent regulation of NMDAR desensitization. FAD mutations, in this region of APP, impair this regulation and consequently enhance NMDAR activity. Thus, by altering the landscape for CaN regulation of NMDA receptors, FAD mutations in APP may contribute to faulty information processing by modifying the dynamic range and temporal window of a critical signal for synaptic plasticity.