Tau downregulates BDNF expression in animal and cellular models of Alzheimer's disease.
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.
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Elyse
E
Rosa
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Sujeivan
S
Mahendram
Dementia Research Unit, The University of New South Wales, Sydney, Australia.
Yazi D
YD
Ke
Dementia Research Unit, The University of New South Wales, Sydney, Australia.
Lars M
LM
Ittner
Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY, USA; Department of Psychiatry, New York University Langone Medical Center, Orangeburg, NY, USA; Department of Neuroscience and Physiology, New York University Langone Medical Center, Orangeburg, NY, USA.
Stephen D
SD
Ginsberg
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada. Electronic address: fahnest@mcmaster.ca.
Margaret
M
Fahnestock
D000544:Alzheimer Disease / Q000235:genetics*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics*; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D024801:Tauopathies; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D016875:tau Proteins
Alzheimer's disease; Amyloid-β; Brain-derived neurotrophic factor; Tau; Tauopathy; Transgenic mice
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