UC San Diego
The Role of PICK1 and PKC alpha in Alzheimer’s Disease
- Author(s): Alfonso, Stephanie
- Advisor(s): Malinow, Roberto
- et al.
Beta amyloid (Aβ), a key component in the pathophysiology of Alzheimer’s disease (AD) is thought to target excitatory synapses early in the disease. We show that excessive GluA2 receptor endocytosis, mediated by a PDZ ligand-domain interaction with protein interacting with C kinase (PICK1) and protein kinase C alpha (PKCα), is required for Aβ to weaken synapses. In mice lacking PICK1 or PKCα, elevations of Aβ fail to depress synaptic transmission in cultured brain slices. We find that reintroducing PKCα in PKCα null mouse slices rescues the Aβ-induced depression. Moreover, the reintroduction of a PDZ mutant form of PKCα does not rescue the synaptic depression. In addition, analysis of whole genome sequencing (WGS) of late onset AD (LOAD) families’ data identified two rare highly penetrant variants in the PKCα gene (PRKCA)
that display increased signaling output relative to wild-type PKCα. We conclude that targeting these proteins could accelerate the development of treatments that could prevent, halt or reverse the course of the disease as well as improve its early detection.