Journal
JOURNAL OF NEUROCHEMISTRY
Volume 108, Issue 6, Pages 1550-1560Publisher
WILEY-BLACKWELL PUBLISHING, INC
DOI: 10.1111/j.1471-4159.2009.05901.x
Keywords
Alzheimer; kinase; metal; oligomer
Categories
Funding
- Alzheimer's Association
- National Institutes of Health [AG17968, AG0212982, K99AR054695]
- UCI Alzheimer's Disease Research Center (ADRC)
- NIH/NIA [P50AG16573]
- Institute for Brain Aging and Dementia (IBAD) [AG00538]
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [K99AR054695] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG021982, P01AG000538, P50AG016573, R01AG017968] Funding Source: NIH RePORTER
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Excess copper exposure is thought to be linked to the development of Alzheimer's disease (AD) neuropathology. However, the mechanism by which copper affects the CNS remains unclear. To investigate the effect of chronic copper exposure on both beta-amyloid and tau pathologies, we treated young triple transgenic (3xTg-AD) mice with 250 ppm copper-containing water for a period of 3 or 9 months. Copper exposure resulted in altered amyloid precursor protein processing; increased accumulation of the amyloid precursor protein and its proteolytic product, C99 fragment, along with increased generation of amyloid-beta peptides and oligomers. These changes were found to be mediated via up-regulation of BACE1 as significant increases in BACE1 levels and deposits were detected around plaques in mice following copper exposure. Furthermore, tau pathology within hippocampal neurons was exacerbated in copper-exposed 3xTg-AD group. Increased tau phosphorylation was closely correlated with aberrant cdk5/p25 activation, suggesting a role for this kinase in the development of copper-induced tau pathology. Taken together, our data suggest that chronic copper exposure accelerates not only amyloid pathology but also tau pathology in a mouse model of AD.
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