Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aß pathology.
Cell Rep
; 35(10): 109228, 2021 06 08.
Article
in En
| MEDLINE
| ID: mdl-34107254
ABSTRACT
The sustained proliferation of microglia is a key hallmark of Alzheimer's disease (AD), accelerating its progression. Here, we aim to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesizing that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We show that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterized by increased ßgal activity, a senescence-associated transcriptional signature, and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. The prevention of early microglial proliferation hinders the development of senescence and DAM, impairing the accumulation of Aß, as well as associated neuritic and synaptic damage. Overall, our results indicate that excessive microglial proliferation leads to the generation of senescent DAM, which contributes to early Aß pathology in AD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Amyloid beta-Peptides
/
Cellular Senescence
/
Microglia
Type of study:
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell Rep
Year:
2021
Document type:
Article
Affiliation country:
United kingdom