CEREBRAL BLOOD FLOW INVERSELY CORRELATES WITH AMYLOID PATHOLOGY AND NEUROINFLAMMATION AFTER REPETITIVE MILD TRAUMATIC BRAIN INJURY

Abstract

disease (AD). Still, the strongest known genetic risk factor for lateonset AD is the inheritance of ApolipoproteinE4 (APOEe4). APOE4/4 carriers have a higher incidence of AD, decreased age of onset, increased Ab deposition and highly affected disease associated microglia. Studies suggest that APOE and APOE-containing lipoproteins are an endogenous ligands for TREM2 in brain, thus raising the possibility of an APOE-TREM2 interaction modulating different aspects of AD pathology, potentially in an isoform-specific manner. This interaction could significantly influence microglia-mediated function, however, the biological significance, and the interconnected role of TREM2 and APOE in AD pathology, is not well understood.Methods: We hypothesize that TREM2 deficiency differentially modulates the pathological phenotype and glial function in AD model mice expressing human APOE3 or APOE4. We first assess changes in cognitive function utilizing novel object recognition, and contextual-cued fear conditioning behavioral paradigms in 6-month-old APP/PS1DE9 mice expressing human APOE3, or APOE4 and in APOE3/Trem2 and APOE4/Trem2 mice, and their non-APP expressing littermates. Results: We reveal that Trem2 deficiency exacerbates cognitive deficits. Brain tissue was collected for histological analysis of pathological phenotype specifically examining: amyloid deposition (6E10, Thioflavin S) and astrocytic (GFAP) and microglia reactivity (IBA1). The impact of TREM2 deficiency on amyloid deposition was confirmed by ELISA. To get further insight in the specific effects of TREM2 deficiency in relationship to expressed APOE isoform, we performed RNA-seq using whole brain tissue followed by comparison to known cell-type specific genetic signatures including known disease associated microglial genes. Conclusions: This study significantly increases our understanding of the interaction between APOE isoforms and TREM2 in association with AD pathology.