Alan Michael Le Grice

Introduction: Alzheimer’s disease (AD) is the most common cause of dementia and is initiated by an imbalance between the formation and clearance of amyloid-β (Aβ).^1,2 The accumulation of Aβ plaques leads to neurodegeneration causing loss of neurons and synapses.^1,2 Microglia function as the primary immune cell in brain tissue. They maintain homeostasis by phagocytosing Aβ and by releasing neurotrophic factors and pro-inflammatory cytokines.² Mitochondrial oxidative stress in microglia has been linked to the development of AD.^1,3 Most the drugs offered for AD help manage symptoms. Treatment options to heal AD may target the toxic accumulations of Aβ peptides and τ proteins.^4,5 The mTOR pathway is a metabolism regulator in microglia and directly affect their ability to clear Aβ.² Methods: Transgenic mice harboring mutations of human amyloid precursor protein, TREM2, and TRPV1 were studied.^2,6,7 Primary microglia culture was obtained, and real-time extracellular acidification rate (EAR) and oxygen consumption rate were measured. The phagocytic activity of microglia was measured by analyzing the uptake of microparticles and concentrations of TNF- α and IL-β. TREM2 knockout mice were treated with AL002c, and TRPV1 knockout mice were treated with capsaicin.  Results: In pure cultured microglia, Aβ exposure leads to an increase in extracellular acidification rate and lactic acid production within hours of exposure.² Chronic exposure to Aβ reduces IL-β and TNF- α expression almost completely.² Additionally, The TREM2 knockout mice were found to have impaired phagocytic activity when exposed to Aβ.^6,7. They are unable to activate glycolysis and have lower EAR. Capsaicin treatment on the TRPV1 receptor for immune tolerant microglia upregulates the mTOR-HIF-1α pathway by phosphorylating AKT and mTOR.⁸ TRPV1-knock out expressed significantly higher concentrations of insoluble Aβ plaques in hippocampal tissues. Conclusion: AD reversal and treatment may be possible by targeting mechanisms in microglial metabolism. The mTOR- HIF-1α pathway is the most notable. When exposed to pathologic agents, AKT is phosphorylated and then phosphorylates mTOR which then produces HIF-1α.² HIF-1α is the key transcriptional regulator that initiates glycolysis. The mTOR pathway controls microglial activation by switching microglia to use glycolysis for rapid energy production. Once activated by Aβ, the microglia may become immune-tolerant and lose their ability to inactivate Aβ.^1,3,4  Regulation of the mTOR pathway and medical treatments that target TREM2 and TRPV1 may be able to increase the fitness of immune-tolerant microglia and reduce AD pathology.^2,7,8

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7. Wang S, Mustafa M, Yuede CM, et al. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. Journal of Experimental Medicine. 2020;217(9). doi:10.1084/jem.20200785
8. Lu J, Zhou W, Dou F, Wang C, Yu Z. TRPV1 sustains microglial metabolic reprogramming in Alzheimer’s disease. EMBO reports. 2021;22(6). doi:10.15252/embr.202052013