TREM2 fuels the anabolic adaptation required for microglial resilience in Alzheimer’s disease

The microglial response to Alzheimer’s disease (AD) pathology has canonically been defined by the transcriptional transition to a Disease-Associated Microglia (DAM) state. However, the specific metabolic programs required to fuel the high-demand functions of this reactive state, such as Aβ encapsulation and clearance, remain obscure. Here, we identify a TREM2-dependent anabolic adaptation as the critical driver of microglial resilience to Aβ pathology. By integrating proteomics, transcriptomics, and in vivo metabolic labeling in the AppNL-G-F mouse model, we demonstrate that plaque-associated microglia undergo a synchronized metabolic shift, coupling enhanced protein synthesis with local mitochondrial biogenesis to support the bioenergetic demands of phagocytosis. We show that TREM2 signaling acts as the essential "metabolic licensor" for this process, driving anabolic remodeling directly at the site of phagocytic activity. In the absence of TREM2, this adaptive response collapses: microglia fail to renew their metabolic machinery, resulting in a state of bioenergetic exhaustion characterized by the accumulation of depolarized mitochondria. Strikingly, we discover that these metabolically compromised cells utilize exophergenesis – the extrusion of large, cargo-filled vesicles – as a compensatory mechanism to purge undigested synaptic and amyloid debris during proteostatic failure. Furthermore, we find that these extruded exophers contain hyperphosphorylated Tau, identifying a potential non-cell-autonomous mechanism for pathology seeding. Single-cell analysis confirms that this anabolic capacity is functionally distinct from the canonical DAM transcriptional signature. Our findings redefine TREM2 not merely as a pathogen sensor, but as a metabolic regulator that safeguards microglial viability and prevents neurotoxic spreading under chronic proteotoxic stress.