Autopsy of a 78-year-old with clinical Alzheimer's dementia shows neurofibrillary tangles in the entorhinal cortex and hippocampus (Braak stage III–IV). The tau protein in neurofibrillary tangles is hyperphosphorylated at specific serine/threonine residues. Which kinase is most consistently implicated in pathological tau hyperphosphorylation in Alzheimer's disease?
- A GSK-3beta (glycogen synthase kinase-3 beta) ✓
- B CDK5 (cyclin-dependent kinase 5)
- C MARK2 (microtubule-affinity regulating kinase 2)
- D DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A)
Explanation
GSK-3beta is the most extensively studied and consistently implicated tau kinase in Alzheimer's disease. It phosphorylates tau at multiple pathological epitopes including Ser199, Ser202, Thr205, Ser396, and Ser404 — residues that are hyperphosphorylated in PHF-tau (paired helical filament tau) of neurofibrillary tangles. GSK-3beta activity is regulated by Wnt signaling and is increased by amyloid-beta through PI3K/Akt pathway inhibition, linking amyloid to tau pathology in the amyloid cascade hypothesis. CDK5 also phosphorylates tau but requires aberrant activators (p25/p35 truncation) seen in neurodegeneration; DYRK1A is particularly relevant in Down syndrome-related AD.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
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