The primary focus of my laboratory is to utilize transgenic mice to study the molecular basis of neurodegeneration, including AD. More specifically, we have developed and characterized genetic models of neurodegeneration by introducing different human genes carrying disease-causing mutations into mice. Importantly, we have demonstrated that these mice develop numerous biochemical, behavioral and neuropathological features of AD and neurodegeneration. We have been continuing to generate additional models and characterize these mice in terms of molecular biological, biochemical, behavioral, and neuropathological criteria that will help us determine the effect of these neurodegenerative disease gene mutations on in vivo biological function and dysfunction. It has become increasing clear that innate immune pathways are involved in AD pathogenesis, which has been a more recent focus of the laboratory. Notably, my laboratory has observed that neuronal-microglial communication through the chemokine fractalkine (CX3CL1) and its cognate receptor, CX3CR1, plays a critical role in AD with opposing effects on the development of the Aβ and microtubule-associated protein tau pathology observed in AD. Furthermore, my laboratory has begun to examine the role of TBI as an environmental risk factor for neurodegeneration and observed a unique neuroinflammatory response in a mouse model of AD exposed to TBI. Finally, in recent pioneering studies, my laboratory has demonstrated that deficiency for TREM2 ameliorates β-amyloid (Aβ) pathology, and lowers expression of inflammatory mediators in an AD mouse model. These provocative findings suggests that TREM2 is essential for accumulation of TREM2+ myeloid cells around Aβ deposits and that these cells express markers consistent with their derivation from peripheral, infiltrating monocytes.