BDNF Signaling in Vascular Dementia and Its Effects on Cerebrovascular Dysfunction, Synaptic Plasticity, and Cholinergic System Abnormality

Abstract

Vascular dementia (VaD) is the second most common type of dementia and is characterized by memory impairment, blood-brain barrier disruption, neuronal cell loss, glia activation, impaired synaptic plasticity, and cholinergic system abnormalities. To effectively prevent and treat VaD a good understanding of the mechanisms underlying its neuropathology is needed. Brain-derived neurotrophic factor (BDNF) is an important neurotrophic factor with multiple functions in the systemic circulation and the central nervous system and is known to regulate neuronal cell survival, synaptic formation, glia activation, and cognitive decline. Recent studies indicate that when compared with normal subjects, patients with VaD have low serum BDNF levels and that BDNF deficiency in the serum and cerebrospinal fluid is an important indicator of VaD. Here, we review current knowledge on the role of BDNF signaling in the pathology of VaD, such as cerebrovascular dysfunction, synaptic dysfunction, and cholinergic system impairment.

Keywords: Brain-derived neurotrophic factor; Cerebrovascular disorders; Cholinergic neurons; Neuronal plasticity; Vascular dementia.

Fig. 1. BDNF/TrkB signaling in vascular system.

BDNF activates PI3K/Akt phosphorylation by binding TrkB receptor, and subsequently reduces MMP9 secretion through the regulation of c-FOS/Jun transcription, and ultimately suppresses vascular permeability. Also, BDNF increases ERK phosphorylation, and subsequently promotes FOXO1 and CREB transcription, and finally boosts cell survival and the production of pro-BDNF by binding TrkB receptor. BDNF/TrkB signaling inhibits p38 phosphorylation, iNOS, and COX2 transcription, finally contributes to the reduction of vascular inflammation by suppressing the secretion of NO, and pro-inflammatory cytokines such as IL-1β, TNF-α, IL-6, and IL-18. BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin-related kinase B; PI3K, phosphoinositide 3-kinases; MMP9, matrix metallopeptidase 9; ERK, extracellular signal-regulated kinase; FOXO1, Forkhead box O1; CREB, cAMP-response element-binding protein; iNOS, inducible nitric oxide synthase; COX2, cyclooxygenase-2; NO, nitric oxide; IL, interleukin; TNF, tumor necrosis factor.

Fig. 2. BDNF/TrkB signaling and cerebrovascular function in vascular dementia.

BDNF/TrkB signaling maintains BBB homeostasis by modulating its permeability through MMPs and NO production, and by regulating revascularization through VEGF signaling. BDNF/TrkB signaling modulates astrocyte morphogenesis and maturation and enhances the neurovascular unit by regulating vascular remodeling. It also controls microglia polarization and function (e.g., phagocytosis and cytokine secretion) and attenuates neuroinflammation. BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin-related kinase B; BBB, blood–brain barrier; MMP, matrix metalloproteinase; NO, nitric oxide; VEGF, vascular endothelial growth factor.

Fig. 3. BDNF/TrkB signaling and memory function in vascular dementia.

During vascular dementia, BDNF/TrkB signaling enhances synaptic plasticity by regulating synaptic transmission, synaptogenesis, synapse formation, synaptic density protein levels, spine maturation, and dendritic outgrowth. It also promotes neuronal cell survival by improving mitochondrial function via protein kinase cAMP-dependent (PKA) signaling and LTP/LTD through the ERK/CREB signaling and GSK3β signaling pathways. Furthermore, BDNF/TrkB signaling regulates neurotransmitter secretion and neuronal cell function through NMDA receptor signaling and controls the cholinergic system via ACh secretion, AChE activity, cholinergic neuron maturation, and cholinergic innervation into the hippocampus. BDNF, brain-derived neurotrophic factor; TrkB, tropomyosin-related kinase B; PKA, protein kinase A; LTP, long-term potentiation; LTD, long-term depression; ERK, extracellular signal-regulated kinase; CREB, cAMP-response element-binding protein; GSK3β, glycogen synthase kinase-3β; NMDA, N-methyl-D-aspartate; ACh, acetylcholine; AChE, acetylcholinesterase.