期刊
NEUROBIOLOGY OF AGING
卷 48, 期 -, 页码 135-142出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neurobiolaging.2016.08.020
关键词
Alzheimer's disease; Tau; Amyloid-beta; Brain-derived neurotrophic factor; Tauopathy; Transgenic mice
资金
- Canadian Institutes of Health Research [MOP-102723]
- Alzheimer Society of Canada [14-30, 17-04]
- Ontario Graduate Scholarship
- NIH [AG043375, AG014449, AG107617]
- Alzheimer's Association [IIRG-12-237253]
- Australian Research Council [DP150104321, DE130101591]
- National Health and Medical Research Council [1081916, 1037746]
- Alzheimer's Australia [DPG14-39]
- Australian Research Council [DE130101591] Funding Source: Australian Research Council
In Alzheimer's disease, soluble tau accumulates and deposits as neurofibrillary tangles (NFTs). However, a precise toxic mechanism of tau is not well understood. We hypothesized that overexpression of wildtype tau downregulates brain-derived neurotrophic factor (BDNF), a neurotrophic peptide essential for learning and memory. Two transgenic mouse models of human tau expression and human tau (hTau40)-transfected human neuroblastoma (SH-SY5Y) cells were used to examine the effect of excess or pathologically modified wild-type human tau on BDNF expression. Both transgenic mouse models, with or without NFTs, as well as hTau40-SH-SY5Y cells significantly downregulated BDNF messenger RNA compared with controls. Similarly, transgenic mice overexpressing amyloid-beta (A beta) significantly downregulated BDNF expression. However, when crossed with tau knockout mice, the resulting animals exhibited BDNF levels that were not statistically different from wild-type mice. These results demonstrate that excess or pathologically modified wild-type human tau downregulates BDNF and that neither a mutation in tau nor the presence of NFTs is required for toxicity. Moreover, our findings suggest that tau at least partially mediates A beta-induced BDNF downregulation. Therefore, Alzheimer's disease treatments targeting A beta alone may not be effective without considering the impact of tau pathology on neurotrophic pathways. (C) 2016 Elsevier Inc. All rights reserved.
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