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[P1–217]: AMPK ISOFORM HOMEOSTASIS DYSREGULATION IN ALZHEIMER's DISEASE
Author(s) -
Zimmermann Helena R.,
Zhou Xueyan,
Ma Tao
Publication year - 2017
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.2017.06.037
Subject(s) - ampk , protein kinase a , amp activated protein kinase , energy homeostasis , heterotrimeric g protein , microbiology and biotechnology , protein subunit , biology , phosphorylation , medicine , neuroscience , endocrinology , signal transduction , biochemistry , g protein , gene , obesity
Background:The etiology of AD is ill-defined, egregiously comprehended and multifactorial, but dietary and environmental factors have been implicated as etiological factors. Epidemiological studies have posited that diets rich in saturated fat increase the risk of AD. Also, palmitic acid (the most common saturated fatty acid in the diet)-enriched diets have shown to cause cognitive impairment as well as learning and memory deficits in a multitude of rodent models. Palmitate-enriched diets and treatment of cultured cells with palmitate results in ER stress in the brain, which has been implicated in amyloid-beta genesis and tau hyperhosphorylation. However, the upstream signaling mechanisms and downstream signaling effectors in the palmitate-induced hyperphosphorylation of tau have not been elucidated. Chronic ER stress results in the induction and activation of C/EBP Homologous Protein (CHOP), a stress-induced transcription factor known to be involved in ER stress-induced deleterious pathophysiological cascades that include oxidative stress, inflammation, and apoptotic cell death. In this study, we determined the role of ER stress in the palmitate-induced hyperphosphorylation of tau as well as the extent to which CHOP mediates this effect, and subsequently delineated and elucidated the signaling mechanisms involved. Methods: We fed nine-month old Chop mice and their C57BL/6J littermates a palmitate-enriched diet or a control-chow diet for three months and determined the extent towhich a palmitate-enriched diet causes ER stress leading to the activation of upstream kinases that culminate in the hyperphosphorylation of tau in the hippocampus. We also determined the role of ER stress-induced CHOP activation in tau hyperphosphorylation induced by exogenous palmitate-treatment of human SH-SY5Y neuroblastoma cells and characterized the proximal and distal signaling cascades by selective knockdown of kinases or ectopic expression of dominant negative kinases that that are involved in the hyperphosphorylation of tau. Results: Our results implicate the ER stress-induced transcription factor CHOP, as an important determinant in initiating and fostering the activation of upstream kinases, GSK3b and ERK1/2, that leads to increased phosphorylation of tau at PHF1 (Ser and Ser) and AT8 (Ser and Thr) epitopes. Conclusions:Our study elucidates novel signaling pathways that are intricately involved in palmitateinduced hyperphosphorylation of tau.