摘要
The hippocampus plays a crucial role in learning and memory,and its progressive deterioration with age is functionally linked to a variety of human neurodegenerative diseases.Yet a systematic profiling of the aging effects on various hippocampal cell types in primates is still missing.Here,we reported a variety of new aging-associated phenotypic changes of the primate hippocampus.These include,in particular,increased DNA damage and heterochromatin erosion with time,alongside loss of proteostasis and elevated inflammation.To understand their cellular and molecular causes,we established the first single-nucleus transcriptomic atlas of primate hippocampal aging.Among the 12 identified cell types,neural transiently amplifying progenitor cell(TAPC)and microglia were most affected by aging.In-depth dissection of gene-expression dynamics revealed impaired TAPC division and compromised neuronal function along the neurogenesis trajectory;additionally elevated pro-inflammatory responses in the aged microglia and oligodendrocyte,as well as dysregulated coagulation pathways in the aged endothelial cells may contribute to a hostile microenvironment for neurogenesis.This rich resource for understanding primate hippocampal aging may provide potential diagnostic biomarkers and therapeutic interventions against age-related neurodegenerative diseases.
基金
This work was supported by the National Key Research and Development Program of China(2020YFA0804000)
the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA16010000)
the National Key Research and Development Program of China(2019YFA0110100,2020YFA0112201,2018 YFC2000100,2017YFA0103304,2017YFA0102802,2018Y FA0107203,2020YFA0803401,and 2019YFA0802202)
the National Natural Science Foundation of China(Grant Nos.81921006,81625009,91749202,81861168034,91949209,92049304,81822018,82071588,92049116,31900523,32000500,31970597,82030037,and 81801534)
the Program of the Beijing Municipal Science and Technology Commissi on(Z191100001519005)
Beijing Natural Science Foundation(Z190019)
the Key Research Program of the Chinese Academy of Sciences(KFZD-SW-221)
K.C.Wong Education Foundation(GJTD-2019-06,GJTD-2019-08)
the International Partnership Program of Chinese Academy of Sciences(152111KYSB20160004)
the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences(2020-JKCS-011)
the State Key Laboratory of Stem Cell and Reproductive Biology,the State Key Laboratory of Membrane Biology,the Milky Way Research Foundation(MWRF),and the Moxie Foundation(for J.C.I.B.).
