期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 78, 期 11, 页码 1066-1072出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlz088
关键词
Brain aging; Cerebrovascular disease; Senescence; Small vessel disease
资金
- Alzheimer's Society (United Kingdom) [PG146/151]
- Alzheimer's Drug Discovery Foundation [20140901]
- Alzheimer's Research UK [PPG2014A-8]
- St George's Hospital Charity
- UK Medical Research Council (MRC) [G1000691]
- Brains for Dementia Research (BDR)
- NIHR Oxford Biomedical Research Centre
- MRC [G1000691, MR/L022656/1] Funding Source: UKRI
Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified senescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcortical white matter of older persons (age 80-96years, n=60) with minimal AD, using antibodies to 2 established senescence markers (H3K9me3, gamma H2AX) and a myocyte marker (hSMM). Within the walls of penetrating arteries (20-300 mu m), we quantified senescence-associated heterochromatic foci (SAHF)-positive nuclei, cell density (nuclei/mu m(2)), and sclerotic index (SI). Senescent-appearing mural cells were present in small arteries of all cases. cSVD cases exhibited a lower proportion of senescent-appearing cells and lower area fraction (AF%) of SAHF-positive nuclei compared to controls (p=0.014, 0.016, respectively). cSVD severity and SI both correlated negatively with AF% (p=0.013, 0.002, respectively). Mural cell density was lower (p<0.001) and SI higher (p<0.001) in cSVD, relative to controls. In conclusion, senescent myocyte-like cells were universal in penetrating arteries of an AD-free cohort aged 80 years and older. Senescent-appearing nuclei were more common in persons aged 80 years and older without cSVD compared to cSVD cases, indicating caution in senolytic drug prescribing. Myocyte senescence and cSVD may represent alternative vessel fates in the aging human brain.
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