To what degree is Alzheimer’s disease driven by immune system aging and consequent dysfunction? The evidence is compelling for increased inflammatory behavior in microglia, innate immune cells of the brain, to be important in neurodegenerative conditions. The state of inflammation in the brain can be driven by inflammatory signaling from the body as well as by mechanisms local to the brain. For example, senescent cells in the aged body produce inflammatory signals that circulate to affect every tissue. It is the overall burden that matters, not just local excesses.

Many issues in the aged immune system arise in the bone marrow, due to changes in the production of immune cells, or damage to the systems of production. In today’s open access paper, researchers show that transplanting bone marrow from young donors mice into aged Alzheimer’s model mice, in order to restore a more youthful production of immune cells, acts to reduce pathology in the brain. Inflammation is reduced and circulating monocytes in the bloodstream outside the brain become more efficient at clearance of the amyloid-β associated with Alzheimer’s disease and this mouse model. The burden of amyloid-β in the brain is also reduced.

While inflammation is important to Alzheimer’s disease pathology, this data suggests that the effect noted here is associated with the dynamic equilibrium between amyloid-β in the brain versus the body. Other groups have demonstrated, in human trials even, that reducing amyloid-β outside the brain leads to a reduction within the brain, validating the peripheral sink hypothesis.

Rejuvenation of peripheral immune cells attenuates Alzheimer’s disease-like pathologies and behavioral deficits in a mouse model

The aged immune system experiences a decline in the production of immune cells, a reduction in immune repertoire diversity, and an increase in dysfunctional immune cells. These changes are collectively referred to as immunosenescence, which not only plays a causal role in driving systemic aging, including brain aging, but also contributes to an increased susceptibility to age-related diseases such as Alzheimer’s disease (AD). Therefore, rejuvenating aged immune cells represents a potential therapeutic strategy for AD.

Therefore, the objective of this study was to investigate the potential of immune rejuvenation as a therapeutic strategy for AD. To achieve this, the immune systems of aged APP/PS1 mice were rejuvenated through young bone marrow transplantation (BMT). Single-cell RNA sequencing revealed that young BMT restored the expression of aging- and AD-related genes in multiple cell types within blood immune cells.

The level of circulating senescence-associated secretory phenotype proteins was decreased following young BMT. Notably, young BMT resulted in a significant reduction in cerebral amyloid-β (Aβ) plaque burden, neuronal degeneration, neuroinflammation, and improvement of behavioral deficits in aged APP/PS1 mice. The ameliorated cerebral amyloidosis was associated with an enhanced Aβ clearance of peripheral monocytes. In conclusion, our study provides evidence that immune system rejuvenation represents a promising therapeutic approach for AD.

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