Transcriptome and proteome profiling reveals TREM2-dependent and -independent glial response and metabolic perturbation in an Alzheimer's mouse model.

Elucidating the intricate molecular mechanisms of Alzheimer's disease (AD) requires a multidimensional analysis incorporating various omics data. In this study, we employed transcriptome and proteome profiling of App, a human APP knock-in model of amyloidosis, at the early and mid-stages of amyloid-beta (Aβ) pathology to delineate the impacts of Aβ deposition on brain cells. By contrasting App mice with TREM2 (Triggering receptor expressed on myeloid cells 2) knockout models, our study further investigates the role of TREM2, a well-known AD risk gene, in influencing microglial responses to Aβ pathology. Our results highlight altered microglial states as a central feature of Aβ pathology, characterized by the significant upregulation of microglia-specific genes related to immune responses such as complement system and antigen presentation, and catabolic pathways such as phagosome formation and lysosome biogenesis. The absence of TREM2 markedly diminishes the induction of these genes, impairs Aβ clearance, and exacerbates dystrophic neurite formation. Importantly, TREM2 is required for the microglial engagement with Aβ plaques and the formation of compact Aβ plaque cores. Furthermore, this study reveals substantial disruptions in energy metabolism and protein synthesis, signaling a shift from anabolism to catabolism in response to Aβ deposition. This metabolic alteration, coupled with a decrease in synaptic protein abundance, occurs independently of TREM2, suggesting the direct effects of Aβ deposition on synaptic integrity and plasticity. In summary, our findings demonstrate altered microglial states and metabolic disruption following Aβ deposition, offering mechanistic insights into Aβ pathology and highlighting the potential of targeting these pathways in AD therapy.