The molecular intersection of TAU, phosphatases and alzheimer's disease

The National Institute on Aging awarded the University of Connecticut Health Center $459,322 on September 15, 2026, under the Aging Research program (CFDA 93.866) to investigate the molecular intersection of tau, phosphatases, and Alzheimer's disease.

The research identifies how serine/threonine protein phosphatases (PPPs) bind tau and regulate tau phosphorylation status in health and disease. The project leverages nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and phosphorylation assays to define which PPP members bind tau, where they bind, and how tau mutations associated with familial tauopathies impact PPP recruitment. The work will characterize PPP-specific tau phosphosites and determine which phosphosites are dephosphorylated by individual PPP members, addressing why PPPs fail to counteract tau hyperphosphorylation despite their role as counteragents to kinases that catalyze abnormal tau phosphorylation in Alzheimer's disease.

Performance occurs in Farmington, Connecticut, with a period of performance from the award date through May 31, 2031. The Aging Research program supports biomedical, social, and behavioral research directed toward understanding the aging process and diseases affecting older populations, with particular emphasis on Alzheimer's disease and related dementias.

Abstract

Aging is typically accompanied by a deterioration of physiological functions, including, for some, cognitive DE- cline. TAU is a neuronal microtubule (MT) associated protein that is essential for stabilizing MTS. TAU hyper- phosphorylation is frequently observed in older humans and in an accelerated fashion in patients with neuro- degenerative diseases. As humans age, regulatory mechanisms that control protein phosphorylation become less effective, leading to abnormal TAU phosphorylation and the subsequent formation of alzheimer disease (ad)-associated TAU filaments. Different SER/THR kinases (GSK3Β, ERK2, CDK5, PKA, marks and camkii) have been shown to catalyze TAU phosphorylation, with GSK3Β activity leading to the most rapid TAU fibril for- mation. However, why SER/THR protein phosphatases (ppps), enzymes that typically counteract the action of SER/THR kinases, fail to counteract TAU hyperphosphorylation is currently entirely unknown. The PPP family of enzymes includes 7 members. Here we will identify how ppps bind TAU and determine PPP-specific TAU phos- phosites to define how ppps regulate TAU phosphorylation status in health and disease. To achieve this, we will leverage the power of NMR spectroscopy, the only technique capable of defining molecular interactions of intrinsically disordered proteins like TAU and with which we are leading experts, cryo-EM and sophisticated phosphorylation and dephosphorylation experiments (we are also experts in the study of phosphatases and kinases, especially the molecular mechanisms they use for substrate recruitment). We will: (1) define which, where and how each PPP binds TAU, (2) define how TAU mutations associated with familial tauopathies impact PPP recruitment, (3) use kinase-specific TAU phosphorylation assays to define which TAU phosphosites are specific dephosphorylated by which PPP, (4) identify if there are phosphosite dependencies on the order and timing of TAU dephosphorylation, (5) elucidate how TAU phosphorylation impacts PPP recruitment and activity, and (6) quantify how the distinct structural states of TAU (soluble/fibrils) alter PPP recruitment and activity. To- gether, these data will create the first phosphorylation/dephosphorylation atlas of TAU and establish a systems biology of TAU phosphorylation and dephosphorylation in ad. Finally, defining how, at a molecular level, ppps recruit and dephosphorylate TAU, and how these interactions are altered in hyperphosphorylated TAU and TAU fibrils, will lead to critically needed novel routes of therapeutic intervention for ad focused on ppps.