Research ArticleAlzheimer’s Disease

Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-β

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Science Signaling  20 Mar 2018:
Vol. 11, Issue 522, eaao6765
DOI: 10.1126/scisignal.aao6765

Nitrosylation links amyloid and tau pathology

Amyloid-β (Aβ), tau aggregates, and nitrosative stress all contribute to the synaptic dysfunction and neurodegeneration associated with the pathology of Alzheimer’s disease. Sen et al. found that the three are functionally linked; Aβ-induced tau acetylation and aggregation by stimulating the enzyme that produces nitric oxide (NO). An increased amount of NO in cortical neurons promoted the nitrosylation of the glycolytic enzyme GAPDH and, subsequently, the activation of the acetylase p300 and inactivation of SIRT1, which together enhanced the pathological acetylation of tau. Treating mice with the GAPDH nitrosylation inhibitor omigapil, which is currently being tested to treat congenital muscular dystrophy, prevented amyloid-induced τ acetylation, memory impairment, and locomotor dysfunction, suggesting that this drug might be explored to treat patients with AD.