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P3‐345: High calorie diet enhanced, but voluntary exercise restored tau pathology in a tauopathy model mouse
Author(s) -
Yoshiyama Yasumasa
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.2010.05.1846
Subject(s) - tauopathy , medicine , endocrinology , genetically modified mouse , triglyceride , obesity , leptin , chemistry , gerontology , neurodegeneration , disease , transgene , biochemistry , cholesterol , gene
Background: Phosphorylation of eukaryotic initiation factor-2a (eIF2a) is increased in Alzheimer’s disease (AD) and it can be phosphorylated by several kinases including double-stranded RNA-dependent protein kinase (PKR), PKR-like endoplasmic reticulum kinase (PERK), amino acids regulated eif2a kinase (GCN2) and heme-regulated eif2a kinase (HRI). Especially, PKR and PERK are activated in AD brain and GCN2 is reported to increase presenilin-1 (PS1) activity. Methods: Primary rat cortical neuron cultures were treated with okadaic-acid. Results: Here, we show that the phosphorylation of eIF2a is also increased and that PKR, PERK and GCN2 are also activated in rat neurons by okadaic acid (OA), a protein phosphatase-2A inhibitor, known to enhance tau phosphorylation, b-amyloid (Ab) deposition and neuronal death, which are the pathological hallmarks of AD. However, PKR inhibitors could not reduce eIF2a phosphorylation and neuronal toxicity despite of PKR inhibition. Conclusions: This implicates that setting PKR as therapeutic target should be made with careful approach and it would be better to target eIF2a phosphorylation itself in AD.