Young bone marrows transplantation rejuvenates immune cells, attenuate cerebral Aβ accumulation and related pathologies in Alzheimer’s disease model mouse

Immunesenescence contributes to systematic aging and participates in the pathogenesis of Alzheimer’s disease (AD). To define the potential of immune rejuvenation in AD therapy, we reconstituted the immune systems of aged APP/PS1 mice through bone marrow transplantation (BMT). Single cell RNA sequencing (ScRNA-seq) of peripheral blood mononuclear cells (PBMCs) indicated that young BMT reverse the expression of aging- and AD-related genes in multiple cell types of PBMCs. Plasma proteome profiling also indicated the reduction of the plasma level of senescence-associated secretory phenotype (SASP) proteins after young BMT. Young BMT significantly reduced central and peripheral Aβ levels, alleviated brain Aβ plaque burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the aged APP/PS1 mice. These effects occurred with the improved Aβ capacity of peripheral monocytes. Collectively, our study demonstrated that rejuvenation of immune system could decrease brain Aβ deposition and other AD-type pathologies, representing a potential therapeutic approach for AD. In order to rejuvenate the peripheral immune system, we established a model of heterochronic BMT. Old (9-month) recipient APP/PS1 mice (YTg BMCs group) were irradiated (with head-shielding) prior to injection of donor bone marrow cells from young (2-month) donor APP/PS1 mice. The mice were feeded for 3 an additional months. To investigate the cellular mechanisms by which young BMT contributes to immune rejuvenation, we isolated and compared, at single cell resolution, the PBMCs from YTg BMCs APP/PS1 mice, with corresponding cells from the young (2-month, control YTg) and old (12-month, control OTg) APP/PS1 mice without BMT.