Proteasome dysfunction induced by p-tau inhibits the cytoplasmic localization and function of HAS1 by blocking its monoubiquitylation.
Alzheimer's disease (AD) is a neurodegenerative disease with neuronal loss and altered extracellular matrix (ECM) components. Here, we confirmed that both a decreased high molecular hyaluronan (HMW-HA) and an increased low molecular hyaluronan (LMW-HA) existed in AD mouse brains. The expression and distribution patterns of the three types of hyaluronan synthases (HASs) were described in AD mice. Immunofluorescence staining of AD mouse brain slices showed increased HAS1 and decreased HAS2 in the soma of neurons. In vitro data indicated that APP-induced phosphorylated tau (p-tau) plays a key role in the reduction and redistribution of HAS1. p-tau competitively inhibited the degradation of polyubiquitinated HAS1 (Ubn-HAS1) in proteasomes, causing the accumulation of Ubn-HAS1 in the cytoplasm. As a consequence of abnormal accumulation, accumulated Ubn-HAS1 was then subjected to the lysosome degradation pathway, and unknown negative feedback loops were activated to downregulate the transcription of HAS1 mRNA. Interestingly, the switch between tau and p-tau modified the subcellular localization of HAS1 between the cytoplasm and the nucleus by regulating the monoubiquitylation of HAS1 and ultimately inhibited the synthesis and release of HMW-HA in neurons.