The Src family kinase YES regulates DNAJB6b chaperone activity to modulate tau aggregation in Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a gradual deterioration of memory. While its prevalence increases with age, the underlying mechanisms remain incompletely understood. Here, we examine the biological consequences of phosphorylation-mediated chaperone activity in AD-associated tau aggregates. Increased phosphorylation of DNAJB6b at Y53 is observed in the brain lysates of AD patients. Our research found that an activated Src family kinase, YES, phosphorylates Y53 in the J-domain of DNAJB6b and enhances the binding between DNAJB6b and Hsp70. The strengthened association between DNAJB6b and Hsp70 may lead to the accumulation of tau aggregates. These findings suggest that up-regulation of YES kinase modifies DNAJB6b and that the resulting alteration in DNAJB6b-dependent tau disaggregation may contribute to an increased risk of AD.