Brain-derived neurotrophic factor in Alzheimer's disease and its pharmaceutical potential

Abstract

Synaptic abnormalities are a cardinal feature of Alzheimer's disease (AD) that are known to arise as the disease progresses. A growing body of evidence suggests that pathological alterations to neuronal circuits and synapses may provide a mechanistic link between amyloid β (Aβ) and tau pathology and thus may serve as an obligatory relay of the cognitive impairment in AD. Brain-derived neurotrophic factors (BDNFs) play an important role in maintaining synaptic plasticity in learning and memory. Considering AD as a synaptic disorder, BDNF has attracted increasing attention as a potential diagnostic biomarker and a therapeutical molecule for AD. Although depletion of BDNF has been linked with Aβ accumulation, tau phosphorylation, neuroinflammation and neuronal apoptosis, the exact mechanisms underlying the effect of impaired BDNF signaling on AD are still unknown. Here, we present an overview of how BDNF genomic structure is connected to factors that regulate BDNF signaling. We then discuss the role of BDNF in AD and the potential of BDNF-targeting therapeutics for AD.

Keywords: Alzheimer’s disease; Amyloid β protein; Brain-derived neurotrophic factor; Neuroinflammation; Neuronal apoptosis; Tau protein.

Fig. 1

Rodent and human BDNF gene structures. a Rodent Bdnf gene structure. b Human BDNF gene structure. Exons are shown as boxes and introns are shown as lines. In both structures, the same color indicates that human exons and rodent exons are homologous. The different exons (Vh and VIIIh) are shown as red box and pink box, respectively. In exon II, there are three transcript variants which are marked as A, B and C. In human BDNF exon IX, there are four different regions that are marked as a, b, c and d. The numbers above the introns and below the exons indicate their base pair sizes. The red arrows indicate the positions in which the transcription starts. ATG represents the sites of the translational start and TAG marks the location of stop codons

Fig. 2

BDNF-related signaling pathways in AD. The pathways related to neuronal excitability are triggered by the interaction between BDNF and TrkB, inducing its dimerization and autophosphorylation of tyrosine residues in the cytoplasmic kinase domain. MEK, PI3K and PLCγ signaling pathways are activated to phosphorylate the transcription factor CREB that mediates transcription of genes essential for synaptic plasticity. GSK3 becomes inactive after phosphorylation, resulting in synthesis of glycogen in the liver cells. When GSK3 remains in its active form, it hyper-phosphorylates tau protein in nerve cells, resulting in the microtubule destabilization and neurofibrillary tangle formation and finally leads to AD. GSK3 also induces the overexpression of Bax to mediate apoptotic injury. Additionally, interaction between pro-BDNF and p75^NTR induces apoptosis through the JNK cascade. The activated NF-κB promotes the expression of β-secretase 1 (BACE1) gene, followed by the overexpression of BACE1 protein and enhanced BACE1 enzyme activity. Aβ is generated from APP by two enzymes: β-secretase (BACE1 is the major one) cuts APP first to produce a C-terminal fragments (CTFs), including C89 and C99. C99 is a membrane bound product. Then γ-secretase (including presenilin, nicastrin, APH-1 and PEN-2) cleaves C99 at a position inside the cell membrane to generate the mature Aβ peptide. In turn, Aβ inhibits the expression of TrkB, leading to neurodegeneration. BDNF: brain-derived neurotrophic factor, p75^NTR: p75 neurotrophin receptor, TrkB: tropomyosin receptor kinase B, Aβ: amyloid β, APP: amyloid β precursor protein, BACE1: β-secretase 1; NRIF: NT receptor interacting factor, JNK: c-Jun N-terminal kinase, TRAF6: TNF receptor associated factor 6, IRAK: Interleukin-1 receptor-associated kinase, IKK: inhibitor of nuclear factor kappa-B kinase, IκB: inhibitor of NF-κB, NF-κB: nuclear factor-κB, TLR4: Toll-like receptor 4, MyD88; Myeloid differentiation primary response gene 88, TNF-α: tumor necrosis factor-α, MEK: mitogen-activated protein kinase kinase, ERK1/2: extracellular signal-regulated protein kinase 1/2, CREB: cAMP-response element binding protein, PI3K: phosphoinositide 3-kinase, Akt: protein kinase B, PLCγ: phospholipase C_γ, PKC: protein kinase C, GSK3β: glycogen synthase kinase-3β, Cyt C: cytocheome C

Fig. 3

Strategies to improve BDNF levels in the brain. The current therapeutic approaches to enhancing  BDNF concentration include endogenous BDNF enhancement and exogenous BDNF supplement. The former one aims to induce endogenous BDNF production or secretion. The latter one attempts to release BDNF in situ or further transport it into target brain regions