SMALL MOLECULES AS A PHARMACOLOGICAL STRATEGY TO PROTECT BDNF RECEPTOR IN ALZHEIMER’S DISEASE

Brain-Derived Neurotrophic Factor (BDNF) is known to promote neuronal protection through the activation of its receptor, TrkB-FL. In Alzheimer’s Disease (AD), this BDNF/TrkB-FL system is compromised due to an amyloid-beta (Aβ)-mediated calpain TrkB-FL cleavage originating two fragments: a truncated receptor (TrkB-T’) and an intracellular fragment (TrkB-ICD) leading to neuroprotection loss. Focusing on the BDNF/TrkB-FL signaling reestablishment as a potential therapeutic strategy for AD, the aim of this work was to search for small compounds able to prevent TrkB-FL cleavage. A computer drug design protocol based on docking prediction, was applied to select the most promising compounds that would bind TrkB-FL at its cleavage site. The top eight compounds were added to primary cortical neuronal rat cultures, with/ without Aβ, to assess their effect on preventing TrkB- FL cleavage. To evaluate the effect of the compounds upon hippocampal synaptic transmission, electrophysiological experiments were performed.
In basal conditions, compound B reduced by ~70% TrkB-ICD/TrkB- FL levels in all studied concentrations compared to control condition (p<0.05,n=5). Compound C, at the 100 nM concentration, decreased TrkB-ICD/TrkB-FL levels in ~70% when compared to its control (p<0.05,n=4). Remarkably, compound H showed potential in decreasing TrkB-ICD/TrkB-FL levels (30%) in the presence of Aβ (p<0.05,n=9). Importantly, compound H did not affect BDNF-mediated phosphorylation of TrkB-FL receptor nor hippocampal synaptic transmission (p>0.05,n=7).
Altogether, compounds B and C prevented TrkB-FL basal cleavage being now important the test them in toxic conditions. Compound H co-incubated with Aβ, prevented TrkB-FL cleavage without interfering with basal synaptic transmission nor TrkB-FL phosphorylation.