Neurotrophins are proteins aiding nerve cell survival, synaptic plasticity, and brain growth. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for learning and memory and are abundant in brain regions. Cognitive decline in aging, linked to diseases like Alzheimer's, may involve BDNF/TrkB signaling changes.
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Introduction of Neurotrophins
Neurotrophins, including nerve growth factor (NGF), BDNF, neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), play vital roles in neuronal plasticity and survival, with specific receptors for each: TrkA for NGF, TrkB for BDNF and NT-4, and TrkC for NT-3. Predominantly expressed in brain regions crucial for learning and memory, BDNF and its receptor TrkB are pivotal. Activation of TrkB by BDNF triggers signaling pathways promoting cell survival, differentiation, and synaptic function regulation. BDNF/TrkB system also fosters neurogenesis. Notably, BDNF exists as proBDNF initially, later cleaved into mature BDNF, differing in affinity for TrkB and p75NTR receptors. While mature neurotrophins favor TrkB, pro-neurotrophins bind to p75NTR, associated with negative neuronal impacts. Dysregulation of neurogenesis and synaptic function contributes to neurodegenerative diseases and aging, highlighting the importance of comprehending neurotrophin mechanisms for potential therapeutic interventions in CNS disorders.
Intracellular Signaling by Neurotrophins
Upon binding to TrkB, BDNF activates three key signaling pathways: PI3k/Akt, ERK, and phospholipase Cγ (PLCγ). These pathways play crucial roles in neuronal differentiation, survival, synaptic function enhancement, neurogenesis maintenance, and protection against cell death, particularly under stressful conditions like oxidative stress. While Akt signaling predominantly supports neuronal survival, PLCγ-mediated intracellular calcium increase is vital for synaptic function, including neurotransmitter release. However, ERK signaling can have positive and negative impacts on CNS function, influencing synaptic protein regulation and neuronal cell death. Truncated isoform receptors of TrkB, notably TrkB.T1, exert independent intracellular signaling and are implicated in various neurological disorders. They may act dominantly against full-length TrkB or scavenge BDNF, affecting synaptic plasticity and neurological function. Additionally, interactions between full-length and truncated TrkB receptors, as well as with the p75NTR receptor, further modulate neurotrophin signaling. Various interactors of p75NTR, including NADE, NRIF1/2, and TRAF family proteins, influence diverse cellular responses such as cell death or survival. The co-receptor function of sortilin with p75NTR is crucial for mediating pro-neurotrophin-induced cell death. Understanding the intricate interactions between different neurotrophin receptors and their signaling pathways is essential for developing targeted therapeutic interventions for neurological disorders.
Fig. 1 Neurotrophins, receptors, and intracellular signaling (Numakawa T., Odaka H. 2022).
Aging, Neurotrophin Signaling, and Neuroinflammation: Impact on Cognitive Function
As individuals age, cognitive function tends to gradually decline, with certain brain regions, particularly the frontal cortex and hippocampus, exhibiting heightened vulnerability. This decline is often accompanied by reductions in brain volume, alterations in dendritic branching patterns, decreased dendritic spines, and diminished adult neurogenesis. Among the various factors implicated in age-related cognitive decline, BDNF signaling has emerged as a prominent player.
BDNF, crucial for synaptic plasticity, neurogenesis, and learning and memory functions, demonstrates alterations in expression and activity with aging. Studies have indicated a reduction in TrkB mRNA expression in the dorsolateral prefrontal cortex of elderly individuals compared to young adults. Additionally, while hippocampal BDNF mRNA levels remain relatively unchanged, the expression of TrkB and its truncated isoform, TrkB.T1, diminishes over the lifespan.
Moreover, alterations in BDNF signaling have been associated with age-related cognitive impairments. Research suggests that a decline in BDNF expression correlates with cognitive deficits in aged animals, while administration of BDNF has been shown to improve cognitive function in aged rodents. Interestingly, the balance between mature BDNF and its precursor, proBDNF, seems critical, with elevated proBDNF levels potentially contributing to memory impairments.
Furthermore, the intricate interplay between neuroinflammation and neurotrophin signaling appears to play a crucial role in age-related cognitive decline. Age-associated changes in microglial activation and subsequent release of proinflammatory cytokines such as IL-1β have been linked to decreased BDNF expression and impaired synaptic plasticity. Additionally, neuroinflammatory processes induced by immune challenges or surgeries have been shown to downregulate BDNF/TrkB signaling in the hippocampus, contributing to cognitive dysfunction.
In Alzheimer's disease (AD), a neurodegenerative disorder primarily affecting the elderly, dysregulation of BDNF signaling is particularly pronounced. Reduced BDNF levels in AD patients' brains are associated with synaptic dysfunction and cognitive decline. Interestingly, therapeutic interventions aimed at restoring BDNF levels have shown promise in preclinical models of AD, highlighting the potential of BDNF-based therapies in mitigating cognitive decline associated with aging and neurodegenerative diseases.
Furthermore, physical exercise has emerged as a promising strategy for enhancing cognitive function in both healthy aging and AD. Exercise-induced upregulation of BDNF expression and downstream signaling pathways, including Akt and CREB, has been linked to improved synaptic plasticity and memory function. Myokines, such as irisin and cathepsin B, released during exercise, have been implicated in mediating these beneficial effects, further emphasizing the therapeutic potential of lifestyle interventions.
In conclusion, age-related cognitive decline is a multifaceted phenomenon influenced by alterations in neurotrophin signaling, neuroinflammation, and lifestyle factors. Understanding the intricate mechanisms underlying these processes holds promise for the development of novel therapeutic strategies aimed at preserving cognitive function and mitigating age-related neurodegenerative disorders. Further research, particularly utilizing human disease models, is crucial for elucidating the complex interplay between aging, neurotrophin signaling, and cognitive function, ultimately paving the way for more effective interventions to promote healthy brain aging.
References
- Numakawa T., Odaka H. The role of neurotrophin signaling in age-related cognitive decline and cognitive diseases. International Journal of Molecular Sciences. 2022, 23(14): 7726.
- Nordvall G., et al. Neurotrophin-targeted therapeutics: A gateway to cognition and more? Drug Discovery Today. 2022, 27(10): 103318.
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