BAC Transgenic Mouse Models of TREM2 to Study Neuroprotective Mechanisms in AD

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Project Summary/Abstract Alzheimer's disease (AD) is the most common neurodegenerative disorder (NDD), and the leading cause of dementia in late adult life. Pathologically it is characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation (e.g. microglia and astrocyte activation). Studies in AD field so far have been focused on proteins that are misfolded and aggregated in the AD brains (e.g. amyloid beta peptide and Tau). However, the role of neuroinflammation in AD pathogenesis remains unclear and underexplored. Recent genome-wide analyses of AD risk genes have lead to the discovery of over 20 genes that modulate AD risk. One exciting insight gained from these studies is that multiple AD risk genes function in the innate immune system, which are known to mediate neuroinflammation in AD and related NDDs. Among the newly discovered AD risk genes, the R47H variant of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) is conferring by far the highest risk (i.e. 2-4 fold higher risk compared to the controls). TREM2 is solely expressed in microglia and peripheral myeloid cells. TREM2 appears to modulate several important function of microglia/myeloid cells, including phagocytosis of debris, suppressing proinflammatory cytokine release, increasing neurotrophic factor synthesis, and supporting microglia survival. However, it remains unclear how TREM2 function or TREM2-R47H dysfunction may modulate AD risk in intact animal models of AD. In this proposal, we developed novel human genomic transgenic models expressing either the wildtype TREM2 variant (BAC-TREM2) or the AD-associated R47H variant (BAC-TREM2-R47H). We designed a series of in vivo genetic experiments, by crossing these models with two existing AD transgenic mouse models, to test our hypothesis that overexpressing TREM2 (hence boosting TREM2 signaling) may promote the beneficial function of microglia and ameliorate AD pathogenesis. Furthermore, we will be able to test whether the TREM2-R47H variant exerts partial loss-of-function or dominant toxicities to modulate AD. In addition, we will apply an integrative genomic approach to compare the transcriptome networks from our mouse models to those derived from AD patients. Finally, we will conduct in vitro signaling assays using primary microglia derived from our models to study how TREM2 and its AD-associated variant may alter signaling. Our study may help to validate the possible neuroprotective effects of microglial TREM2 overexpression in ameliorating AD pathogenesis, and elucidate mechanisms through which TREM2 and its R47H variant may modify AD risk.