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P1‐329: Chronic Type II diabetes differentially change the expression pattern of tau isoforms and hyperphosphorylation depending on tau solubility
Author(s) -
Park Sun Ah,
Jung Hyun Jung
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.2010.05.882
Subject(s) - phosphorylation , western blot , gene isoform , chemistry , medicine , hyperphosphorylation , endocrinology , tau protein , type 2 diabetes , diabetes mellitus , alzheimer's disease , biochemistry , disease , gene
Background: Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is characterized by the presence of intracellular neurofibrillary tangles (NFTs). It is reported that hyperphosphorylated tau and neurofilaments (NFs) which are the major protein components of NFTs might be the result of an imbalanced regulation in protein kinases and protein phosphatases in affected neurons. Accumulating data has demonstrated that PP-2A plays key role in Alzheimer-like hyperphosphorylation of cytosketal proteins and spatial memory retention. However, the mechanisms of spatial memory impairment are not clear, and there is no effective measure to prevent both AD-like pathological changes and spatial memory retention impairment. Methods: In this study, we tested the in vivo effects of melatonin (MT) on these AD-like pathological changes and spatial memory retention deficit in rats by bilateral injection of calyculin A (CA), a potent and specific inhibitor of protein phosphatase-2A (PP-2A) and protein phosphatase-1 (PP-1) into hippocampus. We employed Morris Water Maze test to examine spatial memory of adult rats, used western blot and immunofluorescence to detect alterations of cytosketal proteins phosphorylation, and preand post-synaptic molecules. Results: In this study, we found bilateral hippocampal injection of 2 ml of 16mM CA induced approximately 40% inhibition of PP-2A but no inhibition of PP-1, whereas 32mM CA induced 65% inhibition of PP-2A and 35% inhibition of PP-1. Administration of MT intraperitoneally for 9 consecutive days before bilateral hippocampal injection of 2 ml of 16mM CA could prevent CA-induced synaptophysin loss, memory retention deficits, as well as hyperphosphorylation of tau and neurofilaments (NFs). Furthermore, MT partially reversed the phosphorylation of the catalytic subunit of PP-2A at Tyrosine 307 (Y307), a crucial site negatively regulating the activity of PP-2A. Conclusions: These results suggest that MT could serve as a potential therapeutic agent for preventing AD-like pathological changes and behavioral abnormality via modulating the activity of PP-2A.