PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is the most common neurodegenerative disorder. Although AD patients feature amyloid plaques and neurofibrillary tangles comprising neurotoxic components such as A? and tau within varying brain regions, components which drive neurodegenerative onset during early stages of AD remain uncertain. Interestingly, genome-wide association studies (GWAS) have uncovered a variety of genes enriched in microglia and myeloid cell types, suggesting that AD may be modulated by microglial activation and function. One particular microglial transmembrane component, TREM2 (Triggering Receptor Expressed on Myeloid cells 2) identified by GWAS presents an interesting case for study as mutations in its ectodomain has been implicated in AD, Nasu-Hakola disease, and frontotemporal dementia. Given that these disorders feature neuroinflammatory etiologies, it seems likely that TREM2 microglial function may modulate neurodegenerative onset. TREM2 is proteolytically processed by ADAM proteases to generate soluble TREM2 (sTREM2) ectodomain fragments. Interestingly, sTREM2 levels have been found to be significantly elevated cerebrospinal fluid (CSF) during early stages of AD onset, and its levels correlate with pathogenic CSF markers such as tau and its hyperphosphorylated forms. Despite the potential use of sTREM2 as an early- stage AD biomarker, virtually nothing is known with regards to its role in microglial or neuronal function. Here we present evidence that sTREM2 can enhance microglial survival and activation to enhance proinflammatory cytokine expression. We also find that sTREM2 expression is induced by oligomerized tau, and exposure to sTREM2 can inhibit A? uptake. With these findings, we hypothesize that sTREM2 can act as a modulator of AD onset, and can thereby influence pathogenic A? plaque deposition/clearance, cognitive behavior, and synaptic function. Since little is known with regards to how sTREM2 is generated, and whether sTREM2 or the sTREM2 R47H risk variant can modulate microglial and neuronal function, we present aims here to define neuropathogenic conditions that may influence sTREM2 induction, and trafficking pathways that may influence sTREM2 generation. We will then determine the effects of sTREM2 on microglial and neuronal function. Using inducible microglial and macrophage sTREM2/sTREM2 R47H overexpression mouse models in AD APP/PS1 or tauopathic P301S Tau-Tg backgrounds, we will then determine whether sTREM2 can modulate cognitive behavior, pathological A?/tau accumulation, and synaptic decline. Together, completion of these aims will derive mechanisms of sTREM2 generation, and consequential effects on microglial and neuronal function. Using inducible sTREM2 mouse models, we will also be able to discern sTREM2 modulatory effects on cognitive, pathological and synaptic decline with AD stress. This will provide evidence that correlative increases in sTREM2 levels observed in early-stage AD will influence AD onset and outcome.
- National Institute on Aging: $4,147,115.00