Brain-Derived Neurotrophic Factor Signaling in the Pathophysiology of Alzheimer's Disease: Beneficial Effects of Flavonoids for Neuroprotection

Abstract

The function of the brain-derived neurotrophic factor (BDNF) via activation through its high-affinity receptor Tropomyosin receptor kinase B (TrkB) has a pivotal role in cell differentiation, cell survival, synaptic plasticity, and both embryonic and adult neurogenesis in central nervous system neurons. A number of studies have demonstrated the possible involvement of altered expression and action of the BDNF/TrkB signaling in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In this review, we introduce an essential role of the BDNF and its downstream signaling in neural function. We also review the current evidence on the deregulated the BDNF signaling in the pathophysiology of AD at gene, mRNA, and protein levels. Further, we discuss a potential usefulness of small compounds, including flavonoids, which can stimulate BDNF-related signaling as a BDNF-targeting therapy.

Keywords: Alzheimer’s disease; brain-derived neurotrophic factor; flavonoids; intracellular signaling.

Figure 1

Schematic illustration of the BDNF signaling. The BDNF is initially translated as a precursor (proBDNF). proBDNF preferably binds with the p75-sortilin receptor complex and activates the JNK/caspase3 pathways which cause neural apoptosis and synaptic depression. proBDNF is proteolytically processed to a mature form (mBDNF). Binding of TrkB with mBDNF leads to activation of ERK1/2 and PI3K/Akt pathways to maintain cell survival and synaptic plasticity. mBDNF/TrkB also regulates Ca²⁺ homeostasis and neurotransmission via the PLCγ/IP₃ pathway.

Figure 2

Schematic illustration of dysregulation of the BDNF in Alzheimer’s disease (AD). In the AD brain, mature BDNF (mBDNF) expression is affected by at least three distinct mechanisms, including gene polymorphism (rs6265, BDNF val66met), mRNA translation, and BDNF processing. Through these mechanisms, a reduction of functional mBDNF, impairment of synaptic plasticity/neurogenesis, and then significant decline in memory and learning functions are caused. Black arrow: downregulation.