BAD-Mediated Neuronal Apoptosis and Neuroinflammation Contribute to Alzheimer's Disease Pathology

Alzheimer's disease is the most common progressive neurodegenerative disease. However, the underlying molecular mechanism is incompletely understood. Here we report the identification of the pro-apoptotic BCL-2 family protein BAD as a key regulator for neuronal apoptosis, neuroinflammation and β-amyloid (Aβ) clearance in Alzheimer's disease. The pro-apoptotic activity of BAD is significantly increased in neurons of patients with Alzheimer's disease and 5XFAD mice. Conversely, genetic disruption of Bad alleles restores spatial learning and memory deficits in 5XFAD mice. Mechanistically, phosphorylation and inactivation of BAD by neurotropic factor-activated Akt is abrogated in cortical neurons in patients with Alzheimer's disease and 5XFAD mice, thereby triggering mitochondrial translocation of hypo-phosphorylated BAD to promote neuronal apoptosis and neurodegeneration. Through reactive oxygen species (ROS)-oxidized mitochondrial DNA (mtDNA) axis, BAD also promotes activation of microglial NLRP3 inflammasome, thereby skewing microglia toward neuroinflammatory microglia to inhibit microglial phagocytosis of Aβ plaques in 5XFAD mice. AAV-mediated Bad deletion in hippocampal neurons prevents neuronal apoptosis and rescues memory deficits in 5XFAD mice. In another Alzheimer's disease murine model, APP/PS1 mice, Bad loss also inhibits activation of microglial NLRP3 inflammasome and Aβ deposition, thereby restoring memory deficits. Our results support a model in which BAD contributes to memory deficits and neuropathology in Alzheimer's disease by driving neuronal apoptosis, neuroinflammation but suppressing microglial phagocytosis of Aβ plaques, suggesting that BAD is a potential therapeutic target for Alzheimer's disease.