Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-β-Induced Synaptic Dysfunction and Loss

Dozens of genes have been implicated in late onset Alzheimer's disease (AD) risk, but none has a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation or the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of synaptic LTD is suppressed in Pyk2-null slices. In contrast, deletion of Pyk2 expression does not alter LTP under control conditions. Of relevance forADpathophysiology, Pyk2(-/-) slices are protected from amyloid-beta-oligomer (A beta o)-induced suppression of LTP in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents A beta o-induced suppression of LTP in WT slices. Female and male transgenic AD model mice expressing APPswe/PSEN1 Delta E9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter A beta accumulation or gliosis. Therefore, the Pyk2 risk gene is directly implicated in a neuronal A beta o signaling pathway impairing synaptic anatomy and function.