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 Aβ clearance in AD. BAD pro-apoptotic 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 microglia to inhibit microglial phagocytosis of Aβ 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 Aβ, suggesting that BAD is a potential therapeutic target for AD. [Display omitted] •BAD contributes to neuronal apoptosis in murine models and in patients with AD•Reduced Akt activation is responsible for enhanced neuronal BAD apoptotic activity•Bad loss inhibits Aβ deposition by promoting microglial phagocytosis•BAD promotes microglial NLRP3 inflammasome activation via ROS-mtDNA axis Molecular biology; Neuroscience; Molecular neuroscience.