BDNF Effect upon Apoptosis Induced by Amyloid-Beta Peptide:
Changes in TRKB Receptors Expression
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1
Institute of Molecular Medicine, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Neurosciences Unit, Portugal
Alzheimer’s disease (AD) is characterized by the deposition of amyloid-beta peptide (Aβ), which has been implicated in the neurodegeneration and neuronal loss observed in AD patients (Shimohama, 2000, Apoptosis 5:9). Brain-derived neurotrophic factor (BDNF) is known to protect neurons through activation of TrkB full length (TrkB-FL) receptors. A decrease in both BDNF and TrkB-FL expression (Connor et al., 1997, Mol Brain Res 49:71) and an increase in TrkB truncated receptors (TrkB-Tc), which lacks signaling domain, have been shown to occur in brain tissue from AD patients (Ferrer et al., 1999, J Neuropathol. Exp. Neurol. 58:729). We therefore hypothesized that Aβ could be one of the causes that lead to the changes in BDNF receptor levels in AD. Thus, in this study we evaluated the influence of Aβ upon the expression of full length and truncated forms of the TrkB receptor in cultured neurons. The protective effect of BDNF upon apoptosis induced by Aβ was also assessed.
Primary cortical neuronal cultures were prepared from 18-19-day-old fetuses of Sprague-Dawley rats. Apoptosis was induced by the administration of Aβ25-35 (25μM) on day 4 after plating, and the assays were performed 24h after. BDNF (20 ng/ml) was added 2.5 hours after Aβ25-35. Apoptosis was evaluated through: caspase-3 detection by immunoblot and its activity by spectrophotometric assays. Levels of expression of TrkB receptors were evaluated by immunoblot analysis. The levels of caspase-3 and its activity were low either in neurons under control conditions (without drugs) or in the presence of BDNF alone. When neurons were incubated with Aβ 25-35, there was an approximately a 5-6 fold increase in both the levels and activity of caspase-3 (p<0.01, n=7). When BDNF was added in the presence of Aβ, both formation and activity of caspase-3 were significantly reduced as compared to Aβ alone (-33±5% and -25±6% respectively, n=7, p<0.01). Aβ induced a significant increase in the expression of TrkB- Tc receptors (74±18%, n=7, p<0.01) and a significant decrease in TrkB-FL receptor levels (-37±9%, n=7, p<0.01).
We found for the first time that Aβ increases TrkB-Tc and decreases TrkB-FL levels in cultured neurons. Since BDNF protects neurons against Aβ-induced apoptosis, and since protective actions of BDNF are known to occur through TrkB-FL, the results suggest that Aβ-induced neuronal death may be amplified by the concomitant loss of neuroprotection by BDNF.
Conference:
11th Meeting of the Portuguese Society for Neuroscience, Braga, Portugal, 4 Jun - 6 Jun, 2009.
Presentation Type:
Poster Presentation
Topic:
Neurodegenerative Disorders
Citation:
Jeronimo
AS,
Diogenes
MJ,
Ribeiro
JA and
Sebastiao
AM
(2009). BDNF Effect upon Apoptosis Induced by Amyloid-Beta Peptide:
Changes in TRKB Receptors Expression.
Front. Neurosci.
Conference Abstract:
11th Meeting of the Portuguese Society for Neuroscience.
doi: 10.3389/conf.neuro.01.2009.11.057
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Received:
07 Aug 2009;
Published Online:
07 Aug 2009.
*
Correspondence:
A. S Jeronimo, Institute of Molecular Medicine, University of Lisbon, Institute of Pharmacology and Neurosciences, Faculty of Medicine and Neurosciences Unit, Lisbon, Portugal, nemoABS01@frontiersin.org