Tau protein pathology is central to several neurodegenerative diseases. In Alzheimer's disease, tau forms neurofibrillary tangles (NFTs). The critical pathological tau modification is:

• A Truncation at Glu391 enabling tau to seed fibrils
• B Hyperphosphorylation detaching tau from microtubules, leading to microtubule destabilization and tau self-aggregation into paired helical filaments ✓
• C O-GlcNAcylation causing tau to aggregate into straight filaments
• D SUMOylation preventing proteasomal clearance of tau

Explanation

In Alzheimer's disease, abnormal phosphorylation at multiple Ser/Thr residues (especially Ser202/Thr205, Ser396/Ser404) by kinases including CDK5, GSK-3β, and DYRK1A causes tau to detach from microtubules, disrupting axonal transport. Detached hyperphosphorylated tau self-assembles into paired helical filaments (PHFs) — the structural unit of NFTs — via repeat domain interactions. NFTs follow a stereotyped Braak staging pattern (entorhinal → hippocampus → neocortex). Truncation and O-GlcNAcylation modulate tau but are not the primary mechanism in AD. SUMOylation is studied but not established as the primary driver.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.