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

• Published in: Frontiers in pharmacology Vol. 9; p. 237
• Main Authors: Tanqueiro, Sara R, Ramalho, Rita M, Rodrigues, Tiago M, Lopes, Luísa V, Sebastião, Ana M, Diógenes, Maria J
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 11.04.2018
• Subjects: Alzheimer’s disease; brain-derived neurotrophic factor; extrasynaptic N-methyl-d-aspartate receptors; long-term potentiation; memantine; Pharmacology; TrkB receptor; Alzheimer’s disease; memantine; spine density; TrkB receptor; brain-derived neurotrophic factor; synaptic plasticity; extrasynaptic N-methyl-d-aspartate receptors; long-term potentiation
• ISSN: 1663-9812; 1663-9812
• DOI: 10.3389/fphar.2018.00237

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 Ca -dependent proteases, we hypothesized that excessive intracellular Ca 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 . When calpains were inhibited by calpastatin, BDNF was able to increase the dendritic spine density of neurons exposed to Aβ . 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/Ca /calpains mechanistic involvement in Aβ-triggered BDNF signaling disruption.