Role of Becn2 in modulation of cannabinoid signaling and Alzheimer’s disease

The goal of this proposal is to study whether an autophagy-related protein Becn2 regulates the progression of Alzheimer’s disease (AD) via modulating the cannabinoid receptor signaling. Autophagy is an essential stress-induced lysosomal degradation pathway; yet the role and cellular mechanism of autophagy proteins and autophagy inducers in the regulation of AD remain poorly understood. Our preliminary data show unexpectedly that knockout (KO) of a subunit of the class III phosphatidylinositol 3-kinase (PtdIns3K) complex, Beclin 2/Becn2, leads to reduced amyloid β (Aβ) deposition and improved memory in AD mice, suggesting that autophagy genes play more complex roles in neurodegeneration than originally thought. Thus, it is necessary to uncover the complex functions of autophagy in the regulation of AD progression. We found that Becn2 promotes agonist-induced lysosomal degradation of the cannabinoid receptor 1 (CB1R) and downregulates the CB1R levels in brain. CB1R activation by endogenous or exogenous cannabinoids has recently been suggested to protect against AD in both patients and animal models. Thus, we hypothesize that loss of Becn2 protects AD mice from neurodegeneration by restoring the cannabinoid signaling, and activation of the autophagy machinery by small-molecule compounds not only degrades aggregate-prone proteins, but importantly restores the CB1R function that is downregulated by Becn2. To test the hypothesis, we propose to study the expression (Aim 1), the novel role (Aim 2) and the autophagic regulation (Aim 3) of Becn2 in AD pathogenesis. We have generated neuronal-specific Becn2 KO AD mice, and identified novel candidate autophagy-inducing compounds that improve memory in AD mice through a library screen. We will utilize these new tools to study how Becn2 regulates the CB1R signaling, Aβ neurotoxicity, and the pathogenesis of AD in the brain, and investigate how activating the autophagy pathway regulates the Becn2 interactome and the CB1R function in AD mice. Our studies will shed light on a new genetic link between autophagy and cannabinoid signaling in AD, and will provide understanding on the mechanisms of autophagy activators in the prevention and treatment of AD.