Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats

Univ Montpellier 2, Montpellier, F-34095, France.
Neurobiology of Disease (Impact Factor: 5.08). 08/2008; 31(3):316-26. DOI: 10.1016/j.nbd.2008.05.012
Source: PubMed


We examined the potential protective effect of BDNF against beta-amyloid-induced neurotoxicity in vitro and in vivo in rats. In neuronal cultures, BDNF had specific and dose-response protective effects on neuronal toxicity induced by Abeta(1-42) and Abeta(25-35). It completely reversed the toxic action induced by Abeta(1-42) and partially that induced by Abeta(25-35). These effects involved TrkB receptor activation since they were inhibited by K252a. Catalytic BDNF receptors (TrkB.FL) were localized in vitro in cortical neurons (mRNA and protein). In in vivo experiments, Abeta(25-35) was administered into the indusium griseum or the third ventricle and several parameters were measured 7 days later to evaluate potential Abeta(25-35)/BDNF interactions, i.e. local measurement of BDNF release, number of hippocampal hilar cells expressing SRIH mRNA and assessment of the corpus callosum damage (morphological examination, pyknotic nuclei counting and axon labeling with anti-MBP antibody). We conclude that BDNF possesses neuroprotective properties against toxic effects of Abeta peptides.

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    • "BDNF expression levels are reduced in the brain of AD patients and the importance of BDNF in AD pathophysiology leads to the proposal of BDNF serum levels as a biomarker of AD risk (Gezen-Ak et al., 2013). In vitro studies showed that this neurotrophin reduces neuronal toxicity induced by Aβ 1–42 and Aβ 25–35 (Arancibia et al., 2008) and boosts tau protein de-phosphorylation (Elliott et al., 2005). MG exhibits a peculiar modulation of BDNF/TrkB pathway as it leads to an unexpected up-regulation of BDNF whose protective effects are nullified by a strong down-regulation of TrkB (Di Loreto et al., 2008). "

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    • "Hippocampusspecific BDNF gene knockout or knockdown in rodents results in cognitive impairment in behavioral tests [4] [5]. Moreover, BDNF has neuroprotective effects against diverse neurotoxic insults and neurodegenerative disease models, including Alzheimer's disease (AD) [6] [7]. AD is a common neurodegenerative disease characterized by progressive cognitive deficits, and the accumulation of aggregated amyloid-beta (A) peptide and intracellular neurofibrillary 0304-3940/© 2015 Published by Elsevier Ireland Ltd. tangles which are composed of hyperphosphorylated tau protein [8]. "
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    • "exhibit decreased BDNF levels in these regions ( Phillips et al . , 1991 ; Murray et al . , 1994 ; Amoureux et al . , 1997 ) , which is mirrored by reduced blood serum BDNF levels in AD patients ( Laske et al . , 2006 ) . In vitro experiments demonstrated that BDNF exerts several neuroprotective effects by reducing the cytotoxic effects of Aβ 42 ( Arancibia et al . , 2008 ) and by stimulating the non - amyloidogenic pathway , resulting in a reduction of toxic Aβ species ( Scheuner et al . , 1996 ; Fu et al . , 2002 ; Nishitomi et al . , 2006 ; Thornton et al . , 2006 ; Rohe et al . , 2009 ) . In rodent and primate models of AD it has been shown that acute application of BDNF protein can partially rescue "
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    ABSTRACT: There is increasing evidence that brain-derived neurotrophic factor (BDNF) plays a crucial role in AD pathology. A number of studies demonstrated that AD patients exhibit reduced BDNF levels in the brain and the blood serum, and in addition, several animal-based studies indicated a potential protective effect of BDNF against Aβ-induced neurotoxicity. In order to further investigate the role of BDNF in the etiology of AD, we created a novel mouse model by crossing a well-established AD mouse model (APP/PS1) with a mouse exhibiting a chronic BDNF deficiency (BDNF+/-). This new triple transgenic mouse model enabled us to further analyze the role of BDNF in AD in vivo. We reasoned that in case BDNF has a protective effect against AD pathology, an AD-like phenotype in our new mouse model should occur earlier and/or in more severity than in the APP/PS1-mice. Indeed, the behavioral analysis re-vealed that the APP/PS1-BDNF+/--mice show an earlier onset of learning impairments in a two-way active avoidance task in comparison to APP/PS1- and BDNF+/--mice. However in the Morris water maze test, we could not observe an overall aggrevated impairment in spatial learning and also short-term memory in an object recognition task remained intact in all tested mouse lines. In addition to the behavioral experiments, we analyzed the amyloid plaque pa-thology in the APP/PS1 and APP/PS1-BDNF+/--mice and observed a comparable plaque den-sity in the two genotypes. Moreover, our results revealed a higher plaque density in prefrontal cortical compared to hippocampal brain regions. Our data reveal that higher cognitive tasks requiring the recruitment of cortical networks appear to be more severely affected in our new mouse model than learning tasks requiring mainly sub-cortical networks. Furthermore, our observations of an accelerated impairment in active avoidance learning in APP/PS1-BDNF+/--mice further supports the hypothesis that BDNF deficiency amplifies AD-related cognitive dysfunctions.
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