TSPO deficiency accelerates amyloid pathology and neuroinflammation by impairing microglial phagocytosis.
Zhang H., Wang H., Gao F., Yang J., Xu Y., Fu Y., Cai M., Zhang X., Yang Q., Tong K., Hu Y., Chen H., Ma C., He W., Zhang J.
Increasing evidence has placed inflammation and immune dysfunction at the center of the pathogenesis of Alzheimer's disease (AD). The mitochondrial protein translocator protein (18 kDa) (TSPO) is highly upregulated in microglia and astrocytes in response to inflammatory stimulation. However, the biological action of TSPO in the pathogenesis of AD has not been determined to date. In this study, we showed that TSPO expression was upregulated in brain tissues from AD patients and AD model mice. APP/PS1 mice lacking TSPO generated significantly higher levels of Aβ1-40 and Aβ1-42 peptides and more Aβ plaques, as well as enhanced microglial activation, in the brain. TSPO-deficient microglia cultured in vitro showed a significant decrease in the ability to phagocytose Aβ peptides or latex beads and generated more proinflammatory cytokines (TNF-α and IL-1β) in response to Aβ peptides. Our findings suggest that TSPO has protective functions against neuroinflammation and Aβ pathogenesis in AD. TSPO may be a potential drug target for the development of drugs that have therapeutic or preventive effects in neuroinflammatory diseases.