Abstract: Objective To explore the intrinsic relationship between microglia in Alzheimer′s disease (AD) and natural aging, and their role in mediating microenvironmental proteostasis. Methods Nearly 1.69 million brain single-cell and single-nucleus transcriptomes from 18 public datasets were integrated and annotated using deep generative models. A “transcriptomic aging score” was constructed to compare the transcriptional remodeling of microglia between natural aging and AD models. Multiplex immunofluorescence staining on brain sections was performed to verify the in situ expression of key molecules for proteostasis and lysosomes. A Trem2-deficient model was introduced to explore the regulatory mechanisms. Results AD pathology significantly accelerated the age-dependent accumulation of late-stage disease-associated microglia (DAM-Late). The AD transcriptional profile showed a highly significant positive correlation with natural aging (R=0.481), manifesting as a “pathological amplification” of aging-mediated lipid metabolism and lysosomal programs. Metabolic stress led to the collapse of microglial proteostasis, with a significant increase in the area and number of αB-CRYSTALLIN, CD68, and UBC puncta carried by single cells in the hypothalamus of AD mice. TREM2 acted as a key switch initiating the compensatory program, and its deficiency led to phenotypic decoupling and functional compensation failure. Conclusions The pathological activation of AD microglia significantly amplifies endogenous aging characteristics. Under continuous pathological stress, this adaptive compensation may ultimately mediate severe impairment of proteostasis in the microenvironment and adjacent cells.

Key words: Alzheimer′s disease, microglia, aging, single-cell transcriptomic sequencing