Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies

Abstract

Enhancement of brain-derived neurotrophic factor (BDNF) signalling has great potential in therapy for neurological and psychiatric disorders. This neurotrophin not only attenuates cell death but also promotes neuronal plasticity and function. However, an important challenge to this approach is the persistence of aberrant neurotrophic signalling due to a defective function of the BDNF high-affinity receptor, tropomyosin-related kinase B (TrkB), or downstream effectors. Such changes have been already described in several disorders, but their importance as pathological mechanisms has been frequently underestimated. This review highlights the relevance of an integrative characterization of aberrant BDNF/TrkB pathways for the rational design of therapies that by combining BDNF and TrkB targets could efficiently promote neurotrophic signalling.

Keywords: BDNF; TrkB; excitotoxicity; neurodegeneration; neuroprotection; stroke; therapy.

Figure 1

Function of BDNF/TrkB signalling in the CNS. BDNF binding to TrkB-FL in neurons (left diagram) induces receptor homodimerization and activation, triggering three main signalling pathways: MAPK/ERK (blue), PI3K (pink) and PLCγ (yellow), which regulate several processes central to neuronal function. The ligand-receptor complex can internalize and continue functioning in signalling endosomes. Alternatively, TrkB-T1 can form heterodimers with TrkB-FL and block its transduction cascades. TrkB-T1 is also involved in the regulation of local BDNF concentration (upper diagram) and cell morphology, both in neurons and astrocytes (respectively, left and right diagrams). P, phosphorylation sites important for receptor activation.

Figure 2

Dysfunction of BDNF/TrkB signalling during stroke. Excitotoxicity produced by overstimulation of the NMDARs (a) induces several mechanisms that dysregulate BDNF/TrkB signalling. The inversion of the physiological ratio of TrkB mRNA isoforms (b) and TrkB-FL cleavage by calpain (c) reduce the availability of the catalytic receptor and increase the dominant-negative forms. Furthermore, TrkB-FL and TrkB-T1 undergo a sequential cleavage first by metalloproteinases (d) and then by γ-secretases (e) that shed the receptor ectodomains, which then act as BDNF scavengers (f); BDNF can be further sequestered by increased expression of p75^NTR (g); Consequently, neurotrophic signalling is impaired, a situation aggravated even further by Shp-2 dephosphorylation of TrkB-FL at Tyr515 (h); Neurons in the peri-infarct area promote a survival response as a compensatory mechanism to brain damage and increase the expression of BDNF (i); CTF, C-terminal fragment; ECD, extracellular domain; f32, TrkB-FL calpain-fragment of 32 kDa; ICD, intracellular domain; tTrkB, calpain-truncated TrkB-FL.

Figure 3

Dysfunction of BDNF/TrkB signalling in AD. Patients of AD show a decrease in BDNF levels in several brain areas due to a diminished gene expression (a). The consequent reduction in neurotrophic signalling results in the activation of GSK3β which contributes to tau hyperphosphorylation (b); Moreover, expression of truncated TrkB isoforms is favoured in AD brains by the action of transcription factor SRSF3 (c); Aβ peptide additionally promotes the activities of GSK3β and calpain, which cleaves TrkB-FL receptor near the receptor Shc docking site (d); Additionally, Aβ decreases CREB activity by several mechanisms including a reduction of NMDAR levels (e) and increased PP1 action. f32, TrkB-FL calpain fragment of 32 kDa; P, phosphorylation of tau residues; tTrkB, calpain-truncated TrkB-FL.