Tau phosphorylation from neuronal adaptation to Alzheimer's disease.

Persistent Tau phosphorylation linked to neurodegeneration in Alzheimer's disease may result from dysregulated neuronal adaptive responses rather than a distinct pathological pathway.

• Why it matters: Understanding whether Tau phosphorylation is a normal adaptive process or a sign of disease is crucial for developing targeted therapies for neurodegeneration. The overlap of phosphorylation patterns in both physiological and pathological states creates ambiguity about their roles in health and disease.
• What they did: The authors synthesized findings from human, rodent, and fly brains, as well as neuronal cell models, examining Tau phosphorylation across neurodevelopment, sleep, hibernation, cellular stress, and disease, focusing on phosphorylation patterns and Tau functions.
• The result: They found that while transient phosphorylation is reversible, aging, repeated stress, and amyloid-β-associated stress can lead to persistent pTau accumulation, impaired clearance, aggregation, and neurodegeneration, suggesting that dysregulation of adaptive responses underlies pathological Tau phosphorylation.