Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease

Elyse Rosa, Sujeivan Mahendram, Yazi D. Ke, Lars M. Ittner, Stephen D. Ginsberg, Margaret Fahnestock*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 wild-type 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-β (Aβ) 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 Aβ-induced BDNF downregulation. Therefore, Alzheimer's disease treatments targeting Aβ alone may not be effective without considering the impact of tau pathology on neurotrophic pathways.

Original languageEnglish
Pages (from-to)135-142
Number of pages8
JournalNeurobiology of Aging
Volume48
DOIs
Publication statusPublished - 1 Dec 2016
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Amyloid-β
  • Brain-derived neurotrophic factor
  • Tau
  • Tauopathy
  • Transgenic mice

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