Summary: Rapamycin, a drug approved for cancer and transplant patients, increases amyloid-beta plaques in the brains of an Alzheimer’s disease mouse model.
Source: UT San Antonio
Researchers at The University of Texas Health Science Center at San Antonio (UT Health San Antonio) report that oral rapamycin raises levels of beta (β)-amyloid protein plaques in a mouse model of Alzheimer’s disease. Accumulation of β-amyloid is a central hallmark of Alzheimer’s pathology and is linked to cognitive decline.
Rapamycin is an FDA-approved drug used in oncology and to prevent organ rejection after transplantation. Some publicly available reports have suggested rapamycin might improve learning and memory in aged rodents, but the UT Health San Antonio team found an unexpected effect in their Alzheimer’s model: rapamycin treatment led to a sharp reduction in Trem2 (triggering receptor expressed on myeloid cells 2) protein levels. Trem2 is expressed on microglia, the brain’s resident immune cells responsible for sensing, engulfing and clearing cellular debris and aggregated proteins.
“Trem2 sits on the surface of microglia and helps these cells recognize and ingest β-amyloid,” said senior author Manzoor Bhat, PhD. “When Trem2 levels fall, microglia lose a key mechanism for degrading amyloid, which promotes plaque accumulation.” Dr. Bhat is professor and chair of the Department of Cellular and Integrative Physiology at UT Health San Antonio and vice dean for research at the Joe R. and Teresa Lozano Long School of Medicine.
Targeting microglial signaling
The study, published June 7 in the Journal of Neuroscience, also identified a genetic strategy that counteracts the rapamycin-related loss of Trem2. Lead author Qian Shi, PhD, assistant professor in the Department of Cellular and Integrative Physiology, genetically deleted the Tsc1 gene specifically in microglia. This targeted deletion elevated Trem2 expression in those cells and reduced β-amyloid plaque burden in the Alzheimer’s mouse model.
Prior work shows that loss of Tsc1 activates the mTOR (mammalian target of rapamycin) signaling pathway, whereas rapamycin inhibits mTOR. Given this relationship, the researchers had expected that manipulating Tsc1 or mTOR selectively in microglia could have complex effects. “We anticipated that removing Tsc1 only in microglia might be harmful because mTOR inhibition via rapamycin has therapeutic uses in other disease contexts,” Dr. Shi said. “Instead, boosting microglial mTOR activity by deleting Tsc1 increased Trem2 and improved amyloid clearance.”
These results point to the microglial mTOR-Trem2 axis as a potential drug target: enhancing Trem2 expression in microglia might improve their ability to clear β-amyloid, while systemic mTOR inhibition with rapamycin could inadvertently suppress that capacity.
The experiments were performed in the 5XFAD mouse strain, an established model used to study β-amyloid–driven Alzheimer’s disease. The authors emphasize that their findings are specific to β-amyloid–related pathology in this model and should not be generalized to all forms of Alzheimer’s disease, which can involve distinct mechanisms beyond amyloid accumulation.
Clinical implications and caution
These findings suggest caution when considering rapamycin for people at risk of Alzheimer’s disease characterized by β-amyloid accumulation. “Rapamycin has clear clinical value as an immunosuppressant and cancer therapy,” Dr. Bhat said. “But if the drug reduces expression of Trem2 or other proteins critical for microglial clearance of amyloid, it could worsen β-amyloid pathology. More targeted studies are needed to understand these risks.”
The study underscores the importance of cell-type–specific effects: systemic drugs that modulate central signaling pathways like mTOR may produce beneficial effects in some tissues but unintended harm in others, particularly in the brain’s immune environment. Future research should explore strategies to enhance microglial amyloid clearance—such as selective modulation of Tsc1/mTOR signaling or direct Trem2 upregulation—while avoiding broad immunosuppression that compromises microglial function.
The Bhat laboratory focuses on genetic models of human disease to reveal pathways that control axonal myelination, demyelination and glial cell function. Their work highlights how mTOR signaling in microglia and other glia could be leveraged for therapies in neurological disorders, including Alzheimer’s disease, but also demonstrates the complexity and need for precise targeting.
About this Alzheimer’s disease research news
Author: Will Sansom
Source: UT San Antonio
Contact: Will Sansom – UT San Antonio
Image: The image is in the public domain
Original Research: The findings will appear in Journal of Neuroscience