Microglia TFEB Activation Attenuates Alzheimer's Disease Pathology by Enhancing Autophagy-Lysosomal Function

Alzheimer's disease (AD) is characterized by amyloid-ß (Aß) 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 Aß 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 Aß, 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 Aß 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. Overall design: To investigate transcriptomic alterations associated with TFEB activation in Alzheimer's disease, total RNA was extracted from the cortex and hippocampus of 7-month-old WT, 5xFAD, and 5xTFEB mice and subjected to RNA sequencing.