MICROGLIA AGING IN THE HIPPOCAMPUS ADVANCES THROUGH INTERMEDIATE STATES THAT DRIVE ACTIVATION AND COGNITIVE DECLINE
Jeremy M Shea1, Saul A Villeda1,2,3
1Department of Anatomy, University of California San Francisco, San Francisco, California 94143, USA.
Abstract:
During aging, microglia - the resident macrophages of the brain - exhibit altered phenotypes and contribute to age-related neuroinflammation. While numerous hallmarks of age-related microglia have been elucidated, the progression from homeostasis to dysfunction during the aging process remains unresolved. To bridge this gap in knowledge, we undertook complementary cellular and molecular analyses of microglia in the mouse hippocampus across the adult lifespan and in the experimental aging model of heterochronic parabiosis. Single-cell RNA-Seq and pseudotime analysis revealed age-related transcriptional heterogeneity in hippocampal microglia and identified intermediate states of microglial aging that also emerge following heterochronic parabiosis. We tested the functionality of intermediate stress response states via TGFβ1 and translational states using pharmacological approaches in vitro to reveal their modulation of the progression to an activated state. Furthermore, we utilized single-cell RNA-Seq in conjunction with in vivo adult microglia-specific Tgfb1 conditional genetic knockout mouse models, to demonstrate that microglia advancement through intermediate aging states drives transcriptional inflammatory activation and hippocampal-dependent cognitive decline.
Insights
Aging microglia exhibit intermediate states that drive brain inflammation and cognitive decline. Understanding these microglial aging pathways is key to addressing age-related neuroinflammation and memory loss.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Microglia, the brain's immune cells, change during aging, contributing to neuroinflammation.
- The transition from healthy to dysfunctional microglia during aging is not fully understood.
Purpose of the Study:
- To investigate the progression of microglial aging and its impact on brain function.
- To identify intermediate microglial states during aging and their role in neuroinflammation.
Main Methods:
- Single-cell RNA sequencing (scRNA-Seq) and pseudotime analysis of mouse hippocampal microglia.
- Heterochronic parabiosis model to study aging effects.
- In vitro pharmacological modulation of microglial states.
- In vivo genetic knockout models (Tgfb1) in adult microglia.
Main Results:
- Identified age-related transcriptional heterogeneity and intermediate aging states in hippocampal microglia.
- Demonstrated that these intermediate states, influenced by TGFβ1, can progress to an activated inflammatory phenotype.
- Showed that microglial advancement through aging states drives inflammation and cognitive decline.
Conclusions:
- Microglial aging is a progressive process involving distinct intermediate states.
- TGFβ1 signaling plays a role in modulating microglial aging states and inflammatory activation.
- Targeting these microglial aging pathways may offer therapeutic strategies for age-related cognitive impairment.
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