The Galphaq/phospholipase Cbeta signaling system represses tau aggregation.

Alzheimer's disease is typified by calcium dysfunction and neurofibrillary tangles of tau aggregates along with mitotic proteins. Using PC12 cells as a model system, we determined whether the Galphaq/PLCbeta/ calcium signaling pathway impacts the manifestation of Alzheimer's disease. Down-regulating PLCbeta significantly increases tau protein expression and causes a large increase in tau aggregation. Stimulating Galphaq to activate PLCbeta results in a modest reduction in tau aggregation while inhibiting PLCbeta activity results in a modest enhancement of tau aggregation. These results suggest that PLCbeta may effect tau aggregation by an additional mechanism that is independent of its ability to transduce calcium signals. To this end, we found that a cytosolic population of PLCbeta binds to a mitotic protein found in neurofibrillary tangles, CDK18, which promotes tau phosphorylation and aggregation. Taken together, our studies show that the loss of PLCbeta1 can promote Alzheimer's disease by a combination of its catalytic activity and its interaction with mitotic proteins thus offering an orthogonal method to control tau aggregation.