Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Microglial proliferation is a hallmark of Alzheimer's disease (AD), accelerating disease progression.
• The long-term consequences of sustained microglial proliferation in AD remain incompletely understood.

Purpose of the Study:

• To investigate the impact of early and prolonged microglial proliferation on cellular phenotype and AD pathology.
• To determine if extensive microglial cycling leads to a distinct transcriptional and phenotypic trajectory.

Main Methods:

• Utilized an AD-like mouse model to study microglial proliferation.
• Assessed markers of replicative senescence, including βgal activity and telomere shortening.
• Examined transcriptional signatures and correlated findings with human post-mortem AD brain tissues.

Main Results:

• Early and sustained microglial proliferation induced replicative senescence, characterized by specific transcriptional changes and telomere shortening.
• Senescent microglial profiles and disease-associated microglia (DAM) were observed in both AD models and human AD cases.
• Inhibition of early microglial proliferation prevented senescence and DAM formation, reducing amyloid-beta (Aβ) accumulation and associated neuropathology.

Conclusions:

• Excessive microglial proliferation in AD leads to the development of senescent DAM.
• Senescent DAM contribute to early-stage Aβ pathology and neurotoxicity in Alzheimer's disease.
• Targeting microglial proliferation may offer a therapeutic strategy for early AD intervention.