# Rapamycin Reduces Amyloid‐β Plaques and Improves Behavioral Performance in a Sex‐Dependent Manner in Mouse Models of Amyloidosis

## TL;DR

Rapamycin reduces amyloid plaques and improves memory in Alzheimer's mouse models, especially in females, by enhancing microglial activity.

## Contribution

Demonstrates sex-dependent therapeutic effects of rapamycin on amyloid pathology and microglial function in AD models.

## Key findings

- Rapamycin reduced Aβ plaques and improved memory in 5xFAD and hAPPNL mice.
- Treatment increased microglial recruitment and Aβ clearance, especially in female mice.
- Rapamycin enhanced lysosomal degradation and lipid droplet clearance in microglia.

## Abstract

Alzheimer's disease (AD), the most common form of dementia, lacks effective disease‐modifying treatments. Rapamycin, an mTOR inhibitor with immunomodulatory properties, may mitigate AD pathology by restoring microglial functions.

Rapamycin was orally administered to 2‐month‐old 5xFAD and hAPPNL.

Rapamycin treatment reduced the cerebral Aβ plaque burden, alleviated dystrophic neurites, suppressed glial hyperactivation, and increased plaque‐associated microglial density in both mouse models, with more pronounced effects in female mice. These pathological improvements were associated with attenuated deficits in hippocampal‐dependent memory tasks (spontaneous alternation in the Y‐maze and contextual fear conditioning tasks). Mechanistically, rapamycin enhances microglial lysosomal degradation, promotes lipid droplet clearance in BV2 cells, and increases Aβ phagocytic clearance in primary microglial cells.

Our findings suggest that rapamycin reduces amyloid pathology and associated behavioral deficits in AD mice, an effect associated with enhanced microglial lysosomal activity and Aβ clearance, highlighting its therapeutic potential in AD treatment.

Rapamycin treatment reduced cerebral Aβ plaque burden, alleviated neuritic dystrophy, suppressed glial hyperactivation, and increased plaque‐associated microglial recruitment in amyloidosis mouse models, resulting in improved memory performance. Mechanistically, rapamycin enhanced microglial lysosomal degradation, facilitated lipid droplet clearance in BV2 cells, and promoted Aβ phagocytosis in primary microglia.