BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. However, the underlying molecular mechanism is incompletely understood. Here we report that the pro-apoptotic protein BAD as a key regulator for neuronal apoptosis, neuroinflammation and Ab clearance in AD. BAD proapoptotic activity is significantly increased in neurons of AD patients 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 neurons under AD condition. Through reactive oxygen species (ROS)-oxidized mitochondrial DNA (mtDNA) axis, BAD also promotes microglial NLRP3 inflammasome activation, thereby skewing microglia toward neuroinflammatory micro-glia to inhibit microglial phagocytosis of Ab in AD mice. Our results support a model in which BAD contributes to AD pathologies by driving neuronal apoptosis and neuroinflammation but suppressing microglial phagocytosis of Ab, suggesting that BAD is a potential therapeutic target for AD.

Automated summary

BAD plays a crucial role in driving neuronal apoptosis, neuroinflammation, and inhibiting microglial phagocytosis of Ab in Alzheimer's disease. Inhibition of BAD activity may be a potential therapeutic target for AD.