TREM2 dependent microglial function and dysfunction: A target for therapeutic modulation of Alzheimer's disease and Frontotemporal Dementia

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I want to investigate function and dysfunction of the triggering receptor expressed on myeloid cells 2 (TREM2), which plays a central role in regulating microglial activity and is genetically associated with late onset Alzheimer's disease (AD) and other neurodegenerative disorders. The primary goal of this application is to determine the possibility if TREM2 dependent microglial responses to amyloid plaque pathology may be beneficial and could be exploited to modulate disease progression. Since TREM2 function is associated with phagocytosis, I will investigate if a TREM2 dependent microglial function affects seeding and spreading of amyloid pathology via clearance mechanisms. Moreover, since evidence exists that TREM2, Progranulin (GRN) and Apolipoprotein E (ApoE), which all modulate AD, are strongly upregulated in microglia during disease progression, I will generate mouse reporter lines allowing to determine the spatiotemporal distribution of TREM2, GRN, and ApoE expressing microglia in relation to amyloid plaques or other neuronal lesions with the additional goal to search for functionally distinct microglial subpopulations. Since we recently found that microglia cluster via a TREM2 dependent chemotaxis around amyloid plaques, I hypothesize that microglia may form a microenvironment in which ApoE is selectively enriched. This would drive Amyloid -peptide (A) aggregation but at the same time also allow increased phagocytic clearance of amyloid plaques. As cell autonomous TREM2 signaling depends on its surface transport and is terminated by ADAM 10/17 mediated shedding, modulation of TREM2 cleavage may be a therapeutic strategy to stimulate TREM2 dependent signaling. We recently identified a unique cleavage site of TREM2 C-terminal to histidine 157. Based on this finding I want to generate antibodies, which prevent access of ADAM10/17 to the cleavage site and therefore selectively preserve full-length TREM2 and its cell autonomous signaling activity.