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

Sara R Tanqueiro; Rita M Ramalho; Tiago M Rodrigues; Luísa V Lopes; Ana M Sebastião; Maria J Diógenes

doi:10.3389/fphar.2018.00237

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

Front Pharmacol. 2018 Apr 11:9:237. doi: 10.3389/fphar.2018.00237. eCollection 2018.

Authors

Sara R Tanqueiro^{1

2}, Rita M Ramalho^{1

2}, Tiago M Rodrigues^{1

2

3}, Luísa V Lopes², Ana M Sebastião^{1

2}, Maria J Diógenes^{1

2}

Affiliations

¹ Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
² Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
³ Department of Ophthalmology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.

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 Aβ_25-35. 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.

Keywords: Alzheimer’s disease; TrkB receptor; brain-derived neurotrophic factor; extrasynaptic N-methyl-d-aspartate receptors; long-term potentiation; memantine; spine density; synaptic plasticity.