The Roles of TREM2 Interaction with C1q in Alzheimer's Disease
The major goal of this proposal is to define molecular mechanisms underlying TREM2-C1q interaction and determine how such interaction modulates AD-related pathways in microglia and neurons to influence. Aim 1. To characterize the interaction between TREM2 and C1q both in vitro and in vivo. Aim 2. To determine the functional effects of TREM2 binding to C1q in vitro. Aim 3. To determine the effects of Trem2 deletion on complement activation and related toxicity in AD mouse models. Aim 4. To determine whether the synaptic loss in Trem2-insufficient AD mouse models can be rescued by targeting complement pathway.
TREM2 and C1q are two microglial expressed proteins that play important roles in the pathobiology of AD. Our proposal will address a completely new area of AD pathogenesis by demonstrating how TREM2 and complement C1q interaction regulates microglial and neuronal dynamics to control AD-related toxicity. Our study will establish a critical link between two essential microglial proteins and the gained knowledge should provide guidance in designing mechanism-based therapy by targeting TREM2-C1q.