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P2‐316: Disturbance in AMP‐activated protein kinase (AMPK) signaling pathway in Alzheimer's disease
Author(s) -
Lee Hyoung-Gon,
Lee Hyun-Pil,
Kudo Wataru,
Zhu Xiongwei,
Perry George,
Smith Mark A.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1367
Subject(s) - ampk , protein kinase a , amp activated protein kinase , neuroprotection , neuroscience , signal transduction , mechanism (biology) , phosphorylation , microbiology and biotechnology , biology , philosophy , epistemology
outgrowth, AP-1, or MAPK activation following NGF addition. Neurite outgrowth was assayed by the appearance of neurites and AP-1 or MAPK activation was assayed by transfecting in plasmids where active AP-1 or MAPK induced the synthesis of luciferase, allowing us to measure luciferase activity as a reflection of active AP-1 or MAPK. These assays were also sometimes conducted in the presence of transfected tau expressing plasmids. Results: We found that neurite initiation relied on the presence of tau as tau-depleted cell lines had a lower rate of neurite initiation. More interestingly, re-expressing tau in the tau-depleted cell lines showed that the microtubule-binding activity of tau was not required to restore the neurite initiation activity, which was measured 36 hrs after NGF addition. Turning to earlier activities, we found that at 3 hours after NGF addition, tau-depleted pheochromocytoma cells had a lower level of AP-1 activation that could be rescued if tau were brought back into the cells. Similarly, the tau-depleted cells had a lower level of MAPK activation in response to both NGF and EGF. MAPK activation could be restored if tau, or various tau phospho-mimetic mutants, were brought back into the cells. Microtubule association was not required whereas phospho-thr231 was critical in potentiating MAPK activation. We also found that tau was phosphorylated at thr231 in pheochromocytoma cells responding to NGF. Conclusions: These findings indicate a new functional role for phospho-thr231 tau and a connection between tau and MAPK activation. Since phospho-thr231 tau occurs early during the neurodegenerative process, the potentiation of MAPK activation is likely to have a critical role during neurodegeneration.