Inhibition of NMDA Receptors Prevents the Loss of BDNF Function Induced by Amyloid β

Abstract

Brain-derived neurotrophic factor (BDNF) plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. In Alzheimer’s disease (AD), BDNF signaling is known to be impaired, partially because amyloid β (Aβ) induces truncation of BDNF main receptor, TrkB-full length (TrkB-FL). We have previously shown that such truncation is mediated by calpains, results in the formation of an intracellular domain (ICD) fragment and causes BDNF loss of function. Since calpains are Ca2+-dependent proteases, we hypothesized that excessive intracellular Ca2+ build-up could be due to dysfunctional N-methyl-d-aspartate receptors (NMDARs) activation. To experimentally address this hypothesis, we investigated whether TrkB-FL truncation by calpains and consequent BDNF loss of function could be prevented by NMDAR blockade. We herein demonstrate that a NMDAR antagonist, memantine, prevented excessive calpain activation and TrkB-FL truncation induced by Aβ25–35. When calpains were inhibited by calpastatin, BDNF was able to increase the dendritic spine density of neurons exposed to Aβ25135. Moreover, NMDAR inhibition by memantine also prevented Aβ-driven deleterious impact of BDNF loss of function on structural (spine density) and functional outcomes (synaptic potentiation). Collectively, these findings support NMDAR/Ca2+/calpains mechanistic involvement in Aβ-triggered BDNF signaling disruption.

The Neuroprotective Action of Amidated-Kyotorphin on Amyloid β Peptide-Induced Alzheimer’s Disease Pathophysiology

“…In accordance with previous studies ( Tanqueiro et al., 2018 ), cultured cortical neurons exposed to Aβ 25–35 for 24 h, showed a significant decrease in the number of dendritic protrusions when compared to the control condition (Aβ: 6.58 ± 0.153 vs. control: 8.07 ± 0.153; p < 0.05, two-way ANOVA with Tukey’s multiple comparisons test; n = 5) ( Figure 8C ). Remarkably, the Aβ-induced impairment in the number of dendritic protrusions was absent when neurons were co-treated with 50 nM KTP-NH 2 (Aβ + KTP-NH 2 : 9.60 ± 0.134 vs. control: 8.07 ± 0.153; p < 0.05, two-way ANOVA with Tukey’s multiple comparisons test; n = 5).…”

“…In order to evaluate the neuroprotective effect of drug treatment, spine density was counted as previously done in our lab (Tanqueiro et al, 2018). Briefly, primary neuronal cultures at DIV14 were fixed in 4% PFA in PBS (pH 7.4) for 15 min at RT, after being washed with PBS twice.…”

Adenosine A2A receptors facilitate synaptic NMDA currents in CA1 pyramidal neurons

“…In contrast, neurodegenerative conditions are known to increase activation of NMDA receptors and calciumpermeable AMPA receptors, leading to hippocampal synaptic plasticity impairment (Diógenes et al, 2012;Ferreira et al, 2017;Tanqueiro et al, 2018). There is plenty of evidence that under pathological conditions, A 2A receptor signalling is exacerbated, which contributes to pathogenesis and leads to early cognitive and synaptic dysfunction as well as neurodegeneration (Canas et al, 2009;Cognato et al, 2010;Batalha et al, 2013;Kadowaki-Horita et al, 2013;Kaster et al, 2015;Li et al, 2015a,b;Hu et al, 2016;Laurent et al, 2016;Viana da Silva et al, 2016).…”

Going the Extra (Synaptic) Mile: Excitotoxicity as the Road Toward Neurodegenerative Diseases

“…The overactivation of calpains in AD is associated with functional changes in several proteins involved in neuronal transmission, such as BDNF. Previous reports have shown that Aβ impairs BDNF function in a calpain-dependent manner (Jerónimo-Santos et al, 2015), whereas inhibition of eNMDAR can prevent Aβ-triggered impairment of BDNF action in long-term synaptic potentiation (Tanqueiro et al, 2018).…”