Synapto-depressive effects of amyloid beta require PICK1.

Amyloid beta (A beta), a key component in the pathophysiology of Alzheimer's disease, is thought to target excitatory synapses early in the disease. However, the mechanism by which A beta weakens synapses is not well understood. Here we showed that the PDZ domain protein, protein interacting with C kinase 1 (PICK1), was required for A beta to weaken synapses. In mice lacking PICK1, elevations of A beta failed to depress synaptic transmission in cultured brain slices. In dissociated cultured neurons, A beta failed to reduce surface alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit 2, a subunit of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that binds with PICK1 through a PDZ ligand-domain interaction. Lastly, a novel small molecule (BIO922) discovered through structure-based drug design that targets the specific interactions between GluA2 and PICK1 blocked the effects of A beta on synapses and surface receptors. We concluded that GluA2-PICK1 interactions are a key component of the effects of A beta on synapses.