Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading

Significance Neurofibrillary tangles composed of misfolded and aggregated tau protein are degraded by the autophagy–lysosomal pathway. Microglia play a central role in immune surveillance and neuroinflammation. Here, we reveal that microglial autophagy critically controls microglial metabolic and immune status and also modulates neuronal tau pathology. Autophagy deficiency induces lipid droplet formation and heightened immune response, and these phenotypes can be rescued by activating the lipid efflux system, thus establishing a mechanistic link between lipid accumulation and neuroinflammation. The development of neurofibrillary tangles closely correlates with dementia in Alzheimer’s disease, and our studies provide support that autophagy augmentation may provide therapeutic benefit through targeting both immune cell function and tau pathology.