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Updated: Mar 21, 2026
Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Rapamycin treatment reduces CD11c+ microglia and increases amyloid plaque load in 5xFAD mice
Koliane Ouk1, Francisco Fernández-Klett1, Eileen Schormann2
1Neuropsychiatry and Laboratory of Molecular Psychiatry, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
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.
Insights
Rapamycin, an mTOR inhibitor, worsened amyloid plaque buildup and altered immune cells in a mouse model of Alzheimer's disease (AD). This suggests potential risks for ongoing clinical trials targeting AD with rapamycin.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Mammalian target of rapamycin (mTOR) influences immune regulation and Alzheimer's disease (AD) pathology.
- mTOR inhibitors like rapamycin are being investigated for AD treatment.
Purpose of the Study:
- To investigate rapamycin's effects on immune profiles, proteasome activity, and amyloid pathology in the 5xFAD mouse model of AD.
- To assess behavioral changes related to spontaneous exploration and recognition memory.
Main Methods:
- Utilized the 5xFAD mouse model for amyloid pathology.
- Administered rapamycin and analyzed central/peripheral immune cells via flow cytometry.
- Assessed proteasome activity, amyloid plaque load, and performed behavioral tests (open field, Y-maze).
Main Results:
- Rapamycin decreased CD11c+ microglia in the cortex and hippocampus, correlating with increased amyloid plaque load.
- Observed reduced immunoproteasome content and activity.
- Peripheral blood showed increased granulocytes, while splenic T lymphocytes decreased. No significant behavioral changes were noted.
Conclusions:
- Rapamycin demonstrated detrimental effects on amyloid plaque accumulation and specific microglial subsets in 5xFAD mice.
- Findings are significant given ongoing clinical trials of rapamycin for Alzheimer's disease.
- Further research is needed to understand the complex interplay between mTOR inhibition, neuroinflammation, and AD progression.
