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P1‐077: Early melatonin supplementation modulates Tau hyperphosphorylation in Tg2576 mice
Author(s) -
Wang Jianzhi,
Hu Juan
Publication year - 2008
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.2008.05.663
Subject(s) - melatonin , morris water navigation task , tau protein , epitope , endocrinology , medicine , neuroprotection , hippocampus , hyperphosphorylation , genetically modified mouse , western blot , hippocampal formation , alzheimer's disease , chemistry , transgene , phosphorylation , immunology , antibody , biochemistry , disease , gene
Background: Hyperphosphorylated tau is the major protein subunit of neurofibrillary tangles in Alzheimer’s disease (AD). Until now, there is no effective cure to arrest its hyperphosphorylation. Transgenic mice overexpressing amyloid precursor protein (APP) had normal learning and memory at 4 months of age, but showed impairment by 9 to 10 months of age. The endogenous melatonin play an important role in circadian rhythms regulation, and has various physiological functions including neuromodulatory, vasoactive actions, antioxidative and neuroprotective. Methods: Four-month-old transgenic mice Tg2576 were injected intraperitoneally with melatonin (14mg/kg) every other day for 4 months. We evaluated the long-term influence of melatonin on behavioral, biochemical and neuropathologic changes in Tg2576 mice by Step-down tests, Morris water maze, Immunohistochemistry and Western blotting. Results: The results by Western blot showed that the immunoreaction of tau at Y216/Y279 epitopes of GSK-3 was enhanced significantly in Tg2576 mice, while no obvious change was observed in the total GSK-3. Immuoreaction at Tau-1 epitopes were enhanced, while Tyr307 and pS214 epitopes of PP2A, Tau-5 epitope were weakened after injection of melatonin, suggesting both the activity of PP2A and GSK-3 were elevated. Similar results were observed by immunohistochemistry staining, in which hyperphosphorylated tau was mainly detected in mossy fibers of hippocampal CA3 region. Morris water maze test showed that the latency to find the hidden platform and the distance to reach the platform were shorter in melatonin team compared with the control team. Similar results were also observerd in step-down test. Conclusions: Intraperitoneal injection with melatonin alleviated behavioral deficits in transgenic mice Tg2576. We also demonstrated the the preventive effect of melatonin in Alzheimer-like tau hyperphosphorylation. Our findings suggest early long-term melatonin application is a promising strategy for the treatment of AD.