TYROBP/DAP12: a hub protein linking Alzheimer's disease, microglia, and gut microbiome.

摘要

ABSTRACT Recent genetic and genomic approaches have converged on the role of microglia and inflammation in the pathogenesis of Alzheimer’s disease (AD), potentially presenting novel opportunities for developing prophylaxis and/or therapeutics against AD. In a multiscale gene network analysis, a group at the Icahn School of Medicine at Mount Sinai highlighted TYROBP (aka DAP12) as a key driver gene in microglia activation and AD pathogenesis. TYROBP is one of the first “hits” to emerge from the integrative multi-scale approach to sporadic AD that forms the basis for the AMP-AD Accelerating Medicines Partnership in AD) Program. Our previous studies in the APP/PS1 mouse model of AD pathology suggest that reduction of TYROBP at the mRNA or protein level or inhibition of its activity could represent a potential therapeutic target for AD prevention or treatment by repressing the expression of C1q and the induction of genes involved in the switch from homeostatic microglia to disease-associated microglia. Gut microbiota have also been advanced as a modulator of microglial activity and amyloid pathology. The overall goal of this study is to elucidate the role of TYROBP, the gut microbiota, and their interaction on the regulation of brain physiology and AD. We propose two complementary aims. First, we will identify the role and interaction of TYROBP and the gut microbiota on the regulation of the brain transcriptome during physiological aging or during the onset and progression of amyloid pathology. We will perform RNA sequencing and compare the transcriptomic profiles of WT and APP/PS1 mice that are, respectively either WT or KO at the Tyrobp locus and that harbor either (a) normal gut flora in normal abundance, (b) normal gut flora in reduced abundance or (c) pathological gut microbiota mimicking the flora identified in mouse AD gut. Using 16S rRNA sequencing, we will identify changes in bacterial populations due to gut microbiota-related maneuvers and modulation of TYROBP levels and will attempt to establish a causal link between gut microbiota and the immune-Tyrobp regulated transcriptome. Second, we will define how TYROBP level interacts with the gut microbiota, and how, in turn, these variables modulate AD phenotype and microglia activation. We will perform a panel of behavioral and biochemical analyses in order to determine whether modulation of levels and/or types of gut microbiota, TYROBP expression levels, or the combination of both result in changes in microglial activity and AD pathogenesis. The expected outcome of this study is to generate important novel experimental results that will elucidate the role and the mechanisms of microbiota regulation of microglia activation and AD. This project will also generate important data to determine whether the modulation of different types, levels, and ratios of gut bacteria could modulate TYROBP activity and form the basis for clinical interventions aimed at slowing or preventing AD.