Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.

Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimer's disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimer's beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.

The mitochondrial translocator protein (TSPO) in Alzheimer's disease: Therapeutic and immunomodulatory functions.

The translocator protein (TSPO) has been widely investigated as a PET-imaging biomarker of neuroinflammation and, more recently, as a therapeutic target for the treatment of neurodegenerative disease. TSPO ligands have been shown to exert neuroprotective effects in vivo and in vitro models of Alzheimer's disease (AD), by reducing toxic beta amyloid peptides, and attenuating brain atrophy. Recent transcriptomic and proteomic analyses, and the generation of TSPO-KO mice, have enabled new insights into the mechanistic function of TSPO in AD. Using a multi-omics approach in both TSPO-KO- and TSPO ligand-treated mice, we have demonstrated a key role for TSPO in microglial respiratory metabolism and phagocytosis in AD. In this review, we discuss emerging evidence for therapeutic and immunomodulatory functions of TSPO in AD, and new tools for studying TSPO in the brain.