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Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice [snRNA-seq]

ABSTRACT: There is little understanding of how aging serves as the strongest risk factor for several neurodegenerative diseases. Microglia, undergo age-related maladaptive changes, including increased inflammation, impaired debris clearance, and cellular senescence, yet specific mediators that regulate these processes remain unclear. The aged brain is rejuvenated by youth-associated plasma factors, including tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown acts on the extracellular matrix (ECM) to regulate synaptic plasticity. Given emerging roles for microglia in these processes, we examined the impact of TIMP2 on microglial function. We show that TIMP2 deletion in mice exacerbates microglial phenotypes associated with aging, including transcriptomic changes in cell activation, changes in lysosomal-associated markers and phagocytosis, and elevated levels of stress and inflammatory proteins in the brain extracellular space measured by in vivo microdialysis. Deleting specific cellular pools of TIMP2 in vivo increases microglial CD68 and alters myelin phagocytosis. Treating aged mice with TIMP2 reverses several phenotypes observed in our deletion models, resulting in decreased microglial activation, reduced proportions of proinflammatory microglia, and enhanced phagocytosis of physiological substrates. Our results identify TIMP2 as a modulator of age-associated microglia dysfunction. Harnessing its activity may mitigate detrimental effects of age-associated insults on microglia function.

ORGANISM(S): Mus musculus

PROVIDER: GSE297916 | GEO | 2026/06/01

REPOSITORIES: GEO

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Project description:The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted of additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes—CAPG, LGALS3BP, NRIP1, and P2RY12—were found to share regulatory patterns in response to both aging and extrinsic activation. In-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.

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Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice [snRNA-seq]

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