Dysregulation of TrkB Receptors and BDNF Function by Amyloid-β Peptide is Mediated by Calpain

Abstract

Brain-derived neurotrophic factor (BDNF) and its high-affinity full-length (FL) receptor, TrkB-FL, play a central role in the nervous system by providing trophic support to neurons and regulating synaptic plasticity and memory. TrkB and BDNF signaling are impaired in Alzheimer's disease (AD), a neurodegenerative disease involving accumulation of amyloid-β (Aβ) peptide. We recently showed that Aβ leads to a decrease of TrkB-FL receptor and to an increase of truncated TrkB receptors by an unknown mechanism. In the present study, we found that (1) Aβ selectively increases mRNA levels for the truncated TrkB isoforms without affecting TrkB-FL mRNA levels, (2) Aβ induces a calpain-mediated cleavage on TrkB-FL receptors, downstream of Shc-binding site, originating a new truncated TrkB receptor (TrkB-T') and an intracellular fragment (TrkB-ICD), which is also detected in postmortem human brain samples, (3) Aβ impairs BDNF function in a calpain-dependent way, as assessed by the inability of BDNF to modulate neurotransmitter (GABA and glutamate) release from hippocampal nerve terminals, and long-term potentiation in hippocampal slices. It is concluded that Aβ-induced calpain activation leads to TrkB cleavage and impairment of BDNF neuromodulatory actions.

Adenosine A2A receptor activation is determinant for BDNF actions upon GABA and glutamate release from rat hippocampal synaptosomes

“…Isolation of hippocampal synaptosomes The synaptosomes from Wistar rat hippocampus (two animals for experiment, 6-8 weeks old) were prepared as routinely in our laboratory [9]. Briefly, hippocampi were dissected and homogenized in ice-cold isosmotic sucrose solution (containing 0.32 M sucrose, 1 mM EDTA, 1 mg/ml BSA, and 10 mM HEPES, pH 7.4) and centrifuged at 3000g for 10 min; the supernatant was centrifuged again at 14,000 g for 12 min.…”

“…The synaptosomal fraction corresponds to the top buoyant layer and was collected from the tube. Percoll was removed by two washes with a KHR solution; the whole procedure was conducted at 4°C, and synaptosomes were then kept on ice and used within 3 h as previously described [9].…”

“…[ 3 H] neurotransmitter release from hippocampal synaptosomes [ 3 H]GABA and [ 3 H]glutamate release experiments were performed as previously described [9]. Synaptosomes (protein concentration 1-2 mg/ml) were resuspended in oxygenated Krebs medium (in mM: NaCl 125, KCl 3, NaH 2 H]glutamate (specific activity was 30-60 Ci/mmol) for 5 min and equally layered onto perfusion chambers over Whatman GF/C filters (flow rate, 0.6 ml/min; chamber volume, 90 μl).…”

“…A considerable amount of data has provided molecular and functional evidence for a crosstalk between BDNF and adenosine A 2A receptors (A 2A R) [4]. Accordingly, there is evidence that activation of A 2A R induces the transactivation of TrkB-FL receptors [5,6], TrkB-FL translocation to lipid rafts [7], and regulates BDNF [8] and TrkB-FL levels [9]. Regarding functional evidence, it is clear that the facilitatory actions of BDNF upon CA1 hippocampal synaptic transmission [8,[10][11][12] and synaptic plasticity, both long-term potentiation [9,13,14] and long-term depression [15], are dependent on A 2A R activation.…”

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…Alternatively, a disruption of BDNF signaling would likely reduce or prevent XBP1-dependent amelioration of AD-like pathology (19). In vivo and in vitro studies have demonstrated that oligomeric Aβ alters BDNF expression/function by downregulating its transcripts or impairing axonal transport, with subsequent adverse effects (159)(160)(161)(162)(163)(164)(165). Oligomeric Aβ also reduces BDNF secretion by dendritic cells in humans, thereby decreasing neurotrophic supports for neurons and causing brain damage (166).…”