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

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.

Keywords: Alzheimer's disease; Amyloid-β; Brain-derived neurotrophic factor; Tau; Tauopathy; Transgenic mice.

Figure 1. Expression of wild-type tau in transgenic mice down-regulates BDNF expression

Both 8c-het (*p=0.017) and hTau (**p=0.006) transgenic mice show significantly down-regulated BDNF mRNA compared to non-transgenic controls. There was no significant difference in BDNF expression between TauKO mice and non-transgenic controls (p=0.537). Generalized Linear Model (GLM) and post hoc Tukey’s test. Error bars represent S.E.M. Animals ranged in age from 3–16 months, as indicated in Table 1. n=11–15/group.

Figure 2. Tau-induced BDNF loss is an early event, prior to formation of NFTs in hTau mice

Both 8c-het and hTau transgenic mice show significantly down-regulated BDNF expression, compared to control mice, which appears to begin at the earliest developmental age tested. There is no correlation between BDNF expression (normalized to β-actin) in these tau-expressing transgenic models with age: A) non-transgenic control mice (Pearson correlation r=0.22, p=0.438, B) 8c-het mice (Pearson correlation r=−0.24, p=0.345) or C) hTau animals (Pearson correlation r=−0.12, p=0.690)

Figure 3. Human neuroblastoma cells over-expressing wild-type human tau down-regulate BDNF and BDNF Transcript IV expression

A) SH-SY5Y cells transfected with full-length hTau40-V5-pcDNA3.2 plasmid (H) express V5-tagged protein that was absent from non-transfected control cells (C) (Student’s t-test, **p<0.00001). Tau over-expressing SH-SY5Y cells express significantly decreased B) BDNF mRNA (normalized to β-actin) compared to controls (Student’s t-test, **p<0.0001) and C) BDNF Transcript IV mRNA (normalized to β-actin) compared to controls (Student’s t-test, **p<0.0001). Error bars represent S.E.M. n=9/group

Figure 4. Tau partially mediates Aβ-induced down-regulation of BDNF expression

Over-expression of Aβ in APP23 transgenic mice resulted in a significant reduction of BDNF mRNA compared to non-transgenic animals (one-way ANOVA and post hoc Tukey’s test *p=0.017). However, APP23xTauKO mice expressed levels of BDNF mRNA that were intermediate between wild-type and APP23 mice and were no different from non-transgenic animals (one-way ANOVA and post hoc Tukey’s test p=0.162). Error bars represent S.E.M. n=5–9/group