Rapamycin treatment reduces CD11c⁺ microglia and increases amyloid plaque load in 5xFAD mice

Exp Neurol. 2026 Mar 18;401:115709. doi: 10.1016/j.expneurol.2026.115709. Online ahead of print.

ABSTRACT

The mammalian target of rapamycin (mTOR) is involved in immune regulation and in the metabolism of β-amyloid (Aβ) and tau peptides in Alzheimer's disease (AD). In this study, we investigated the effects of the mTOR inhibitor, rapamycin, on central and peripheral immune profiles, proteasome activity, Aβ pathology, and spontaneous exploratory activity and place recognition in the 5xFAD mouse model of amyloid pathology. Using flow cytometry, we found that rapamycin induced changes in immune cell numbers and phenotypes in 5xFAD mice, notably a significant decrease of CD11c⁺ microglia in cortex and hippocampus of 5xFAD mice. This was associated with increased Aβ plaque load. Concomitantly, we observed a decrease in immunoproteasome content and activity. In peripheral blood, rapamycin treatment resulted in higher percentages of granulocytes, whereas splenic T lymphocytes were reduced. No changes in the open field and modified Y-maze tests were observed following rapamycin treatment in wild-type and 5xFAD mice. Our results reveal detrimental effects of rapamycin on amyloid plaque accumulation and CD11c⁺ disease-associated microglial subsets in cortex and hippocampus of 5xFAD mice, which is an important finding given two ongoing phase 2 clinical studies of rapamycin treatment in AD.

PMID:41855773 | DOI:10.1016/j.expneurol.2026.115709