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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    • "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.
    Frontiers in Behavioral Neuroscience 03/2015; 9:00058. DOI:10.3389/fnbeh.2015.00058 · 3.27 Impact Factor
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    • "Neuronal depolarization therefore augmented the effect of BDNF on dendritic branching. BDNF has been shown to promote neuronal survival in vitro (Arancibia et al., 2008; Mattson et al., 1995). Here, we examined whether depolarization alters the neuronal survival function of BDNF in a model of glutamate-induced neuronal excitotoxicity (Almeida et al., 2005; Mattson et al., 1995). "
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    ABSTRACT: Differential kinetics of the same signaling pathway may elicit different cellular outcomes. Here we show that high-frequency neuronal activity converts BDNF-induced TrkB signaling from a transient to a sustained mode. A prior depolarization (15 mM KCl, 1 hour) resulted in a long-lasting (>24 hours) activation of TrkB receptor and its downstream signals which otherwise lasts less than an hour. The LTP-inducing theta-burst stimulation but not the LTD-inducing low-frequency stimulation also induced sustained activation of TrkB. This sustained signaling facilitated dendritic branching and rescued neuronal apoptosis induced by glutamate. The change in TrkB signaling kinetics is mediated by calcium elevation and CaMKII activation, leading to an increase in TrkB expression on the neuronal surface. Physical exercise also alters the kinetics of TrkB phosphorylation induced by exogenous BDNF. Sustained TrkB signaling may serve as a key mechanism underlying synergistic effects of neuronal activity and BDNF.
    Journal of Cell Science 03/2014; 127(10). DOI:10.1242/jcs.139964 · 5.43 Impact Factor
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    • "Based on that, they stated that such phenomenon possibly occurs due to a compensatory mechanism that would happen in the initial stages of dementia. The increase in BDNF in vivo could represent an attempt to rescue neurons from damage and diminish the amyloid burden since it was able to reverse the toxic effect of Ab in vitro (Arancibia et al., 2008). Laske et al. (2006) proposed that peripheral levels of BDNF would increase in the early stages of dementia and decrease according to the severity of the neurodegeneration. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Neurotrophic factors and inflammatory markers may play considerable roles in AD. In this study we measured, through Enzyme-Linked Immunosorbent Assay, the plasma levels of brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF) and neuronal growth factor (NGF), as well as tumor necrosis factor-alpha soluble receptors, sTNFR1 and sTNFR2, and soluble intercellular adhesion molecule 1 (sICAM-1), in 50 AD patients, 37 patients with mild cognitive impairment (MCI) and 56 healthy elderly controls. BDNF levels, expressed as median and interquartile range, were higher for AD patients (2545.3, 1497.4-4153.4 pg/ml) compared to controls (1503.8, 802.3-2378.4 pg/ml), P < 0.001. sICAM-1 was also higher in AD patients. sTNFR1 levels were increased in AD when compared to controls and also to MCI. GDNF, NGF and sTNFR2 levels showed no significant differences among the studied groups. The increase in BDNF might reflect a compensatory mechanism against early neurodegeneration and seems to be related to inflammation. sTNFR1 appears to mark not only the inflammatory state but also differentiates between MCI and AD, which may be an additional tool for differentiating degrees of cognitive impairment.
    Journal of Psychiatric Research 02/2014; 53(1). DOI:10.1016/j.jpsychires.2014.01.019 · 3.96 Impact Factor
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