Work

A Novel Phosphorylated Tau Conformer Implicated in the Tauopathy Pathogenesis of Human Neurons

Year: 2025

Type: article

Abstract: Alzheimer's disease (AD) is a neurodegenerative disorder with no effective treatments. Hyperphosphorylation of tau protein contributes to neurodegeneration in AD. Previous studies have identified pT231-tau in the cis conformation as an early driver of neurodegeneration in tauopathy models. Here, we identify a novel neurotoxic pT231-tau conformer in human AD neurons, distinct from both cis and trans conformations, which we propose as the gauche pT231-tau conformer. Notably, levels of this conformer were elevated in neurons subjected to aging-associated stress. In order to confirm the stress, we examined p21 accumulation in both human iPSC-derived and mouse cortical neurons under aging stress. Targeted elimination of the gauche pT231-tau conformer mitigated neurodegeneration in human AD cultures. These findings suggest the gauche pT231-tau conformer plays a key role in tau-mediated neurodegeneration and may be a potential therapeutic target for AD.

Source: Biomolecules

DOI: 10.3390/biom15040585

Authors: Nahid Tofigh, Sadaf Agahi, Gholamhossein Riazi, Mahboobeh Ghalamkar Moazzam, Koorosh Shahpasand

Institutions: Royan Institute, University of Tehran, Academic Center for Education, Culture and Research, Tehran University of Medical Sciences, University of Minnesota

Language: English

Topic: Alzheimer's disease research and treatments

Subfield: Physiology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,258