# Microglia TFEB activation attenuates Alzheimer’s disease pathology by enhancing autophagy-lysosomal function

## TL;DR

Activating TFEB in microglia improves Alzheimer’s disease by boosting waste clearance and reducing brain inflammation.

## Contribution

This study shows that microglial TFEB activation specifically enhances Aβ clearance and reduces neuroinflammation in Alzheimer’s.

## Key findings

- Microglial TFEB overexpression reduces amyloid burden in key brain regions of 5xFAD mice.
- TFEB activation rescues memory deficits in both male and female 5xTFEB mice.
- Transcriptomic analysis reveals upregulated autophagy and reduced inflammatory signaling.

## Abstract

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type–specific therapeutic strategy for AD and related neurodegenerative disorders.

The online version contains supplementary material available at 10.1186/s12974-026-03728-z.