Neurotrophic factors are secreted that support the survival, development, and function of neurons throughout the nervous system. In the context of neurodegeneration, these signaling molecules play critical roles in maintaining neuronal health, promoting synaptic plasticity, and protecting against pathological processes characteristic of such as Alzheimer's disease (AD) and Parkinson's disease (PD). The dysfunction or deficiency of neurotrophic signaling has emerged as a key pathological mechanism underlying progressive neuronal loss in these disorders.
Neurotrophic factors are secreted that support the survival, development, and function of neurons throughout the nervous system. In the context of neurodegeneration, these signaling molecules play critical roles in maintaining neuronal health, promoting synaptic plasticity, and protecting against pathological processes characteristic of such as Alzheimer's disease (AD) and Parkinson's disease (PD). The dysfunction or deficiency of neurotrophic signaling has emerged as a key pathological mechanism underlying progressive neuronal loss in these disorders.
The nerve growth factor family of neurotrophins includes NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4)[@levimontalcini1987]. These share structural homology and signal through the Trk family of receptor tyrosine kinases (TrkA, TrkB, TrkC) as well as the p75NTR receptor, which can mediate both pro-survival and pro-apoptotic signals depending on receptor expression patterns and ligand availability[@chao1995].
Nerve Growth Factor (NGF) was the first neurotrophic factor discovered and primarily supports the survival and function of sympathetic neurons and sensory neurons, particularly those involved in pain and temperature perception[@crowley1994]. In the central nervous system, NGF is produced by cortical and hippocampal neurons and is internalized and transported retrogradely to cell bodies, where it exerts trophic effects on basal forebrain cholinergic neurons that project to the [hippocampus](/brain-regions/hippocampus) and [cortex](/brain-regions/cortex)[@sofroniew2001]. These cholinergic neurons are particularly vulnerable in AD, and NGF signaling impairment contributes to the characteristic cholinergic deficit observed in AD patients[@schliebs2011].
Brain-Derived Neurotrophic Factor (BDNF) is the most widely expressed neurotrophin in the central nervous system and exerts pleiotropic effects on neuronal survival, synaptic plasticity, and cognitive function[@lu2008]. BDNF signals primarily through TrkB receptor and influences excitatory synaptic transmission by enhancing glutamate release and postsynaptic responses[@poo2001]. BDNF plays crucial roles in hippocampal synaptic plasticity, including [long-term potentiation](/entities/long-term-potentiation) (LTP), which underlies learning and memory formation[@lu2013]. Decreased BDNF expression and signaling have been documented in AD, PD, and HD brains, suggesting that BDNF deficiency contributes to synaptic dysfunction and neuronal loss across multiple neurodegenerative conditions[@zuccato2009].
Neurotrophin-3 (NT-3) supports the survival of various neuronal populations, including proprioceptive sensory neurons, sympathetic neurons, and central cholinergic neurons[@maisonpierre1990]. NT-3 signals primarily through TrkC receptor and plays important roles in neural development, particularly in the differentiation of neuronal subtypes and the establishment of synaptic connections[@farias1994].
Neurotrophin-4 (NT-4) signals through TrkB receptor and influences the survival of specific neuronal populations, including motor neurons and sensory neurons[@liu1995]. NT-4 has been studied for its potential neuroprotective effects in PD models, where it promotes the survival of dopaminergic neurons[@gavazzi1997].
The GDNF family includes GDNF, neurturin (NRTN), artemin (ARTN), and persephin (PSPN)[@airaksinen2002]. These signal through the GFRα family of glycosylphosphatidylinositol-anchored co-receptors (GFRα1-4) in combination with the Ret receptor tyrosine kinase[@jing1996].
GDNF was initially identified for its potent survival effects on dopaminergic neurons and has been extensively studied as a potential therapeutic agent for PD[@lin1993]. GDNF promotes the survival and maintenance of dopaminergic neurons in the substantia nigra pars compacta, the neuronal population that degenerates in PD[@choilundberg1997]. However, clinical trials delivering GDNF to PD patients have yielded mixed results, likely due to challenges in achieving adequate delivery across the [blood-brain barrier](/entities/blood-brain-barrier)[@nuttin2019].
Neurturin (NRTN) is closely related to GDNF and also promotes dopaminergic neuron survival. Clinical trials using neurturin (CERE-120) have investigated its safety and efficacy in PD patients, with some studies showing modest benefits in motor function[@bartus2015].
Ciliary Neurotrophic Factor (CNTF) was initially identified for its survival effects on chick ciliary ganglia neurons and has since been shown to support various neuronal populations[@lin2019]. CNTF signals through a complex consisting of CNTFRα, gp130, and LIFR, activating the JAK-STAT signaling pathway[@stahl1994]. CNTF has been studied for potential therapeutic applications in ALS and other neurodegenerative conditions[@sleigh2020].
Insulin-like Growth Factors (IGFs) including IGF-1 and IGF-2 play important roles in neuronal survival and function. IGF-1 promotes synaptic plasticity and has been studied for potential neuroprotective effects in AD and PD[@bassil2014]. The IGF-1 signaling pathway intersects with multiple pathways implicated in neurodegeneration, including AKT/mTOR signaling and protein homeostasis[@cohen2008].
Neurotrophic factors exert their effects by binding to specific cell surface receptors, triggering dimerization and autophosphorylation of the receptor tyrosine kinases[@chao1992]. This activates multiple downstream signaling cascades, including the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, the mitogen-activated protein kinase (MAPK/ERK) pathway, and the phospholipase C-γ (PLCγ) pathway[@patapoutian2001].
The PI3K/AKT pathway is a major pro-survival signaling cascade activated by neurotrophin binding. AKT phosphorylation leads to activation of mTORC1, which promotes protein synthesis and cellular growth[@franke2008]. AKT also phosphorylates and inhibits pro-apoptotic including BAD and [GSK-3β](/entities/gsk3-beta), linking neurotrophic signaling to the regulation of [apoptosis](/entities/apoptosis)[@datta1999].
The MAPK/ERK pathway regulates neuronal differentiation, synaptic plasticity, and cell survival. ERK activation leads to phosphorylation of transcription factors including CREB (cAMP response element-binding protein), promoting the expression of genes involved in neuronal survival and synaptic function[@impey1996]. The MAPK pathway also plays important roles in [NMDA receptor](/entities/nmda-receptor) regulation and synaptic plasticity in the hippocampus[@sweatt2001].
The PLCγ pathway leads to generation of inositol trisphosphate (IP3) and diacylglycerol (DAG), which mobilize intracellular calcium and activate protein kinase C (PKC)[@nishizuka1992]. This pathway contributes to synaptic plasticity and modulates neurotransmitter release[@yang1999].
Neurotrophic factors are internalized at distal synapses and transported retrogradely to the cell body through dynein-dependent transport along microtubules[@cosker2008]. This retrograde transport delivers activated signaling endosomes containing the activated Trk receptor complex to the nucleus, where they influence gene expression programs that promote neuronal survival[@hibbert2006]. Disruption of axonal transport represents a common feature of many neurodegenerative conditions and may impair neurotrophic signaling in disease states[@roy2009].
Neurotrophic factor signaling intersects with multiple pathways directly implicated in neurodegenerative processes. The PI3K/AKT pathway inhibits GSK-3β, a kinase that hyperphosphorylates [tau protein](/entities/tau-protein) and promotes tau aggregation in AD[@avila2012]. BDNF/TrkB signaling also suppresses amyloid-beta-induced neurotoxicity through activation of downstream survival pathways[@yu2018].
In PD, neurotrophic factor signaling interacts with α-synuclein pathology. GDNF signaling can protect dopaminergic neurons against α-synuclein-induced toxicity, and conversely, α-synuclein aggregation can impair neurotrophic signaling pathways[@kim2018]. This bidirectional relationship suggests that enhancing neurotrophic signaling may be particularly beneficial in the presence of protein aggregation pathology.
Multiple neurotrophic factor systems are impaired in AD. Basal forebrain cholinergic neurons, which depend on NGF for survival, show early degeneration in AD, contributing to memory deficits[@coyle1983]. NGF levels are reduced in AD brain tissue, and impaired NGF axonal transport has been documented in AD mouse models and human patients[@mufson2012].
BDNF expression is decreased in AD hippocampus and cortex, and this reduction correlates with cognitive impairment[@peng2005]. BDNF promoter activity is inhibited by amyloid-beta through multiple , including transcriptional repression and disrupted chromatin remodeling[@lesne2020]. Restoring BDNF signaling has shown promise in AD mouse models, where BDNF delivery improves synaptic function and cognitive performance[@nagahara2011].
The selective vulnerability of dopaminergic neurons in the substantia nigra pars compacta in PD has motivated extensive investigation of GDNF family signaling in this condition. GDNF and neurturin are produced in the striatum and support dopaminergic neuron survival through Ret signaling[@paratcha2002]. Studies show reduced GFRα1 and Ret expression in PD substantia nigra, potentially contributing to reduced responsiveness to GDNF family ligands[@ho2021].
BDNF is expressed in dopaminergic neurons and supports their survival through TrkB signaling. Polymorphisms in the BDNF gene have been associated with PD risk and age of onset, suggesting that BDNF signaling modifies PD susceptibility[@kim2013].
Neurotrophic factor signaling is impaired in ALS, and enhancing neurotrophic support has been explored as a therapeutic strategy. CNTF and BDNF have been studied in ALS clinical trials, though systemic delivery challenges have limited efficacy[@controlled1999]. GDNF delivered via gene therapy approaches has shown promise in ALS mouse models, protecting motor neurons from degeneration[@sun2018].
The relationship between neurotrophic factor signaling and TDP-43 pathology, the hallmark protein aggregation in ALS, has been investigated. TDP-43 can disrupt BDNF expression and signaling, potentially linking protein pathology to trophic factor deficiency[@barker2019].
HD is associated with profound neurotrophic factor deficiency. BDNF expression is reduced in HD brain tissue, and this reduction is thought to contribute to the characteristic striatal neuron loss[@zuccato2015]. The mutant [huntingtin protein](/entities/huntingtin-protein) disrupts BDNF transcription by sequestering transcription factors including REST, leading to decreased BDNF expression in HD neurons[@zuccato2007].
GDNF and CNTF have shown neuroprotective effects in HD models. GDNF delivery protects striatal neurons against mutant huntingtin-induced toxicity, and CNTF delivery improves behavioral outcomes in HD mouse models[@mcgarry2018].
Direct delivery of neurotrophic factors to the brain has been explored through multiple approaches. Intracerebral infusion of GDNF showed promise in PD animal models but faced challenges in human trials including delivery logistics and potential side effects[@kordower2000]. AAV-mediated gene therapy enables sustained expression of neurotrophic factors and has entered clinical trials for PD (AAV2-GDNF, CERE-120)[@bartus2019].
Small molecule compounds that enhance neurotrophic factor expression represent an alternative approach. The NTF-inducing compound 4-methylcatechol (4-MC) increases BDNF expression and has shown neuroprotective effects in animal models[@saito2008].
Small molecule agonists of Trk receptors have been developed to bypass the need for protein delivery. ANA-12 is a selective TrkB agonist that enhances BDNF signaling and improves cognitive function in AD mouse models[@cazorla2011]. GSB-197 and other TrkB agonists are being investigated for potential neuroprotective effects in neurodegenerative [@lee2011].
Compounds that enhance downstream neurotrophic signaling pathways represent another therapeutic approach. PI3K/AKT activators, including the small molecule SC79, enhance neuronal survival in vitro and in vivo[@zhang2017]. GSK-3β inhibitors enhance neurotrophic signaling by preventing inhibition of AKT and promoting downstream pro-survival effects[@lovestone2019].
AAV-mediated gene delivery enables targeted expression of neurotrophic factors in specific brain regions. AAV2-GDNF delivery to the striatum of PD patients has shown safety and potential efficacy in Phase I trials[@heiss2019]. More recently, AAV2-NTN (CERE-120) has been investigated, with clinical trials demonstrating safety and suggesting modest motor benefits[@bartus2013].
Cerebrospinal fluid (CSF) levels of neurotrophic factors and their receptors provide information about CNS neurotrophic signaling status. CSF BDNF is reduced in AD and correlates with cognitive impairment[@portt2011]. CSF NGF levels have been studied as a marker of cholinergic system integrity in AD[@mocsai2019].
Peripheral blood levels of neurotrophic factors may provide accessible . Serum BDNF is increased in acute exercise but chronically reduced in neurodegenerative conditions[@eyileten2017]. The relationship between peripheral and central neurotrophic factor levels remains an area of investigation.
PET ligands that bind to neurotrophic factor receptors could enable visualization of receptor expression in vivo. TrkB PET ligands have been developed and validated in preclinical models[@wakatsuki2022]. Such imaging approaches could help identify patients most likely to benefit from neurotrophic-based therapies.
The tropomyosin receptor kinase (Trk) family (TrkA, TrkB, TrkC) represents the primary signaling receptors for neurotrophins. Upon ligand binding, Trk receptors dimerize and autophosphorylate tyrosine residues in their intracellular domains, creating docking sites for adaptor that initiate downstream signaling cascades.
The PI3K/Akt pathway is a major pro-survival signaling cascade activated by Trk receptors. Phosphoinositide 3-kinase (PI3K) generates phosphatidylinositol (3,4,5)-trisphosphate (PIP3), which recruits Akt (protein kinase B) to the plasma membrane. Akt then phosphorylates numerous substrates that promote cell survival, including BAD, caspase-9, and forkhead transcription factors. In neurodegeneration, the PI3K/Akt pathway is often compromised, reducing pro-survival signaling and increasing vulnerability to apoptotic stimuli.
The MAPK/ERK pathway regulates gene transcription through activation of Ras, Raf, MEK, and ERK kinases. ERK1/2 phosphorylate transcription factors including CREB (cAMP response element-binding protein), which promotes the expression of genes involved in synaptic plasticity and neuronal survival. Dysregulation of this pathway has been implicated in both AD and PD pathogenesis.
The PLCγ pathway generates diacylglycerol (DAG) and inositol trisphosphate (IP3) through phospholipase C-gamma (PLCγ) activation. These second messengers activate protein kinase C (PKC) and release calcium from intracellular stores, respectively, leading to activation of various downstream effectors that modulate synaptic transmission and plasticity.
The p75 neurotrophin receptor (p75NTR) can bind all neurotrophins with similar affinity and can function as a co-receptor with Trk receptors or signal independently. When expressed without Trk receptors, p75NTR can mediate apoptosis in certain contexts, adding complexity to the neurotrophin signaling network. In neurodegeneration, altered p75NTR expression and signaling may contribute to neuronal loss.
The development of neurotrophin-based therapies for neurodegenerative faces several challenges. The blood-brain barrier limits the delivery of large protein therapeutics to the central nervous system. Additionally, the short half-life of neurotrophic requires repeated administration or sustained delivery systems. These challenges have motivated various approaches:
Several pharmaceutical companies have developed BDNF mimetics and TrkB agonists. Small molecule TrkB agonists have shown promise in preclinical models of AD and depression. These compounds aim to bypass the delivery challenges of BDNF protein while providing similar therapeutic benefits.
Neurotrophic factor signaling represents a fundamental mechanism for neuronal survival and function that becomes dysregulated in neurodegenerative . The evidence linking BDNF, NGF, and GDNF to the pathogenesis of AD and PD has motivated extensive research into neurotrophin-based therapeutic approaches. While significant challenges remain in translating these findings to clinical treatments, the neurotrophic signaling pathway remains a promising target for disease-modifying therapies in neurodegeneration.