Serendipitously discovered as an antifungal agent from soil samples, rapamycin is used as an immunosuppressant in patients with transplantation, cancer, and neurological disorders, and is believed to reduce age-related cognitive decline. Extensive studies on the mechanism of rapamycin action have shown that it inhibits a key signaling pathway called the mechanistic target of rapamycin (mTOR), which regulates cellular metabolism and differentiation.
A new study in mice now shows rapamycin taken orally inhibits the mTOR pathway in microglial cells in the brain to down-regulate a gene called Trem2 and subsequently reduce the clearance of β-amyloid plaques.
“Trem2 is a receptor located on the surface of microglia. It enables these cells to engulf and degrade β-amyloid. Loss of Trem2 in microglia impairs the vital function of amyloid degradation, which in turn causes a buildup of β-amyloid plaques,” said senior author of the study, Manzoor Bhat, PhD, professor of cellular and integrative physiology at the University of Texas Health Science Center at San Antonio (UT Health San Antonio) and vice dean for research of the university’s school of medicine.
The findings, published in a Journal of Neuroscience article titled, “Microglial mTOR Activation Upregulates Trem2 and Enhances β-Amyloid Plaque Clearance in the 5XFAD Alzheimer’s Disease Model,” have significant implications for public health since they indicate that in Alzheimer’s disease (AD) patients, rapamycin treatment could aggravate beta-amyloid related pathologies.
“Rapamycin may have benefits in terms of suppressing the immune system and as a tumor suppressor,” Bhat said. “But in a situation where it negatively impacts the expression of Trem2 or other critical proteins, it may have a detrimental effect. We caution that rapamycin’s benefits in β-amyloid-associated Alzheimer’s must be studied more carefully.”
In addition to cautioning against the use of rapamycin in patients with AD, the study also highlights a new route to cut down beta-amyloid plaques in the brain. The lead author of the study, Qian Shi, PhD, assistant professor in the department of cellular and integrative physiology at UT Health San Antonio, deleted a gene called Tsc1 in microglia that is a negative regulator of the mTOR pathway. This increased Trem2 levels in microglia, reduced the loss of microscopic spines on the cell surface, and decreased β-amyloid plaques in both sexes of an AD mouse model.
“We expected that selective loss of Tsc1, only in microglia and not in neurons or other cells, would have negative consequences because inhibiting mTOR with rapamycin has known therapeutic uses in some disease models,” said Shi. “But the opposite was occurring.”
Selective suppression of Tsc1 in microglia, therefore, offers a therapeutic strategy to activate the mTOR pathway and increase β-amyloid uptake and plaque clearance in AD patients. The findings are only relevant to β-amyloid and not generalizable to other AD pathologies, Bhat pointed out.
