Astrocytic TPK1 mitigates amyloid pathology via TFEB-mediated endocytosis

Alzheimer's disease (AD), the leading cause of dementia, is characterized by amyloid-beta (Aβ) plaques, neurofibrillary tangles, and progressive neurodegeneration. Deregulation of glial cell activity plays an important role in the amyloid pathology. However, it is still unclear how changes in astrocytes contribute to Aβ deposition and clearance in AD. Here, we showed that deficiency of astrocytic thiamine pyrophosphokinase 1 (Tpk1), exacerbated Aβ burden leading to exacerbated spatial memory deficits in a mouse model of AD. While selective overexpression of Tpk1 in astrocytes ameliorated cognitive decline and significantly reduced hippocampal and cortical Aβ plaque burden. Enhanced Tpk1 expression augmented astrocyte endocytic capacity. Mechanistically, Tpk1-promoted endocytic activity depended on the activation of transcription factor EB (TFEB)-mediated pathways. Collectively, our findings demonstrate that astrocytic TPK1 mitigates cognitive impairment in 5xFAD mice by upregulating TFEB expression, thereby enhancing astrocyte-mediated engulfment and degradation of neurotoxic aggregates, including Aβ. This study suggests that astrocytic TPK1/TFEB pathway is a promising target for developing disease-modifying AD therapies.