Alzheimer's disease (AD) is a progressive neurodegenerative disorder with hallmarks of ?-amyloid (A?) deposits in the brain. Recent GWA studies have shown that an R47H mutation of TREM2 is associated with a substantial increase in the risk of developing AD. TREM2 is a cell surface receptor expressed by microglia and other myeloid cells and triggers intracellular tyrosine phosphorylation signals through the adapter DAP12. To date, it is unclear how the R47H mutation affects TREM2 function and contributes to AD pathogenesis. Our preliminary data demonstrate that TREM2 deficiency and haploinsufficiency result in a lack of reactive microglia around A? plaques and A? accumulation in the 5XFAD mouse model of AD. We also show that TREM2 binds lipids that are exposed during A? deposition and neuronal cell death and that the R47H mutation impairs the ability of TREM2 to bind these lipids. Thus, we propose that TREM2 is a sensor for damage- associated lipids, which activates the microglial response to A? and thereby limits A? deposition and neuronal loss. The R47H mutation may affect TREM2 function, facilitating A? accumulation. To pursue this model we propose three aims.
In Aim 1 we will test the hypothesis that R47H mutation is sufficient to cause defective microgliosis and A? accumulation using newly generated transgenic mice in which the endogenous Trem2 gene is replaced with either the common or R47H human TREM2 allele. These mice will be crossed with 5XFAD mice to induce spontaneous A? accumulation.
In Aim 2 we will investigate the cellular mechanisms of defective microgliosis. Our preliminary data show that TREM2 deficiency affects activation and survival of microglia, making them vulnerable to limited CSF-1 supply. We will test the hypothesis that TREM2 deficiency also impacts microglia proliferation during A? deposition and that intracerebral administration of CSF-1 rescues microglia survival/proliferation in the absence of TREM2. We will also perform parabiosis experiments to test whether TREM2 is required for migration of blood monocytes into the CNS to generate emergency microglia to clear A? deposits.
In Aim3 we present striking preliminary data showing that TREM2-deficiency impairs mitochondrial respiration as well as spare respiratory and glycolytic capacity of microglia. We also show that the microglial response to A? accumulation requires increased mitochondrial respiration and glycolysis. We therefore hypothesize that TREM2 directly affects metabolic programming of microglia, and that TREM2- deficiency precludes them from meeting the ATP demand required for A? clearance. To test this, we will determine how TREM2 may control microglial metabolism by triggering the PI3K-mTOR pathway and/or tyrosine phosphorylation of key enzymes that control glycolysis. We originally identified and characterized TREM2 and previously generated TREM2 antibodies and mouse models. We have exciting preliminary data and have assembled an integrated interdisciplinary team of experts in AD, microglia imaging, metabolomics and signaling. Thus, we are confident that this project will critically impact the field of microglia biology and AD.
Alzheimer's Disease (AD) is a progressive and irreversible brain disease that affects more than five million Americans. The causes of the disease are presently unknown and there is no cure or therapy that can significantly slow the progression of AD. Recent studies have shown that a mutation in a receptor expressed by cells of the brain that belong to the immune system is associated with significantly higher risk of developing AD. In this grant application we propose to investigate how the mutation in this receptor and the cells that express it modulate AD.
|Wang, Yaming; Ulland, Tyler K; Ulrich, Jason D et al. (2016) TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 213:667-75|
|Song, Wilbur; Hooli, Basavaraj; Mullin, Kristina et al. (2016) Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement :|
|Ulland, Tyler K; Wang, Yaming; Colonna, Marco (2015) Regulation of microglial survival and proliferation in health and diseases. Semin Immunol 27:410-5|