Neuroprotective function of microglial TREM2 in TDP43-related neurodegeneration

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PROJECT SUMMARY Studies using rodent models of amyotrophic lateral sclerosis (ALS) demonstrate microglia are neuroprotective during the early stages of the disease. However, the underlying molecular mechanisms are still largely unknown. Triggering receptor expressed on myeloid cell 2 (TREM2) play crucial roles in microglial proliferation, migration, and phagocytosis. TREM2 variants are linked to increased risk for neurodegenerative diseases, including Alzheimer’s disease and ALS. Thus, here we will investigate the how TREM2 mediates microglia neuroprotective effects in ALS-like proteinopathy induced by viral overexpression of TAR-DNA binding protein 43 kDa (TDP-43) and transgenic TDP-43 mouse models. Our preliminary data indicate that TDP-43 overexpression results in microglia activation in mice. We also observed that reactive microglia interact with TDP-43 positive neurons. More interestingly, TREM2 deficiency leads to more severe neuronal loss, motor dysfunction and lower survival induced by TDP- 43 overexpression. Therefore, we hypothesize that TREM2 mediates microglial neuroprotection by sensing and phagocytosing TDP-43 during ALS-like motor neuron degeneration. We will test this hypothesis in the following two Aims: Aim 1: Determine how TREM2 mediates microglial response to TDP-43 proteinopathy. In this aim, we will (a) assess how TREM2 deficiency affects microglial response to TDP-43-induced pathology by confocal imaging of brain slices and two-photon in vivo imaging of live brain. Then we will (b) test whether microglial response occurs through direct binding of TDP-43 to TREM2 and whether such binding activates TREM2 and its signaling pathways. According to our hypothesis, we predict that microglial responsiveness to TDP-43 pathology is through TREM2 and downstream signaling. Aim 2: Determine how TREM2 exerts microglial neuroprotection in TDP-43 proteinopathy. In this aim, we will (a) assess neuronal loss and motor dysfunction as well as the level of TDP-43 proteinopathy to investigate the function of microglial TREM2 in neuroprotection after TDP-43 overexpression. Furthermore, we will (b) use in vivo imaging to determine whether microglial TREM2 facilitates TDP-43 protein clearance and thus protect against spread of the TDP-43 pathology. According to our hypothesis, we predict that microglial TREM2 is neuroprotection in TDP-43 proteinopathy through promoting phagocytic clearance of TDP-43. The current study is the first attempt to study the causal link between microglial TREM2 and TDP-43 proteinopathy in ALS-like neurodegeneration. The mechanism may also serve as a common model to address the function of microglia in TDP-43 related neurological diseases, such as frontotemporal degeneration and Alzheimer’s disease.