BDNF/Neurotrophin Signaling Pathway in Neurodegeneration
Brain-derived neurotrophic factor (BDNF) and other neurotrophins represent a critical family of growth factors that support neuronal survival, plasticity, and function throughout the lifespan. The neurotrophin signaling system, comprising BDNF, nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4), plays essential roles in development, maintenance, and repair of the nervous system. Dysregulation of neurotrophin signaling has emerged as a fundamental mechanism in the pathogenesis of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and other neurodegenerative disorders. This page provides a comprehensive examination of neurotrophin signaling mechanisms, their alterations in neurodegenerative disease, and therapeutic strategies targeting this pathway.
Pathway Diagram
Mermaid diagram (expand to render)
Overview of Neurotrophin Signaling
The Neurotrophin Family
The neurotrophin family consists of structurally related secreted proteins that bind to specific receptor tyrosine kinases:
| Neurotrophin | Primary Receptor | Primary Functions |
|--------------|------------------|-------------------|
| BDNF | TrkB (NTRK2) | Synaptic plasticity, memory, neuronal survival |
| NGF | TrkA (NTRK1) | Sympathetic neurons, sensory neurons, cholinergic neurons |
| NT-3 | TrkC (NTRK3) | Motor neuron survival, proprioception |
| NT-4 | TrkB | Motor neuron survival, synaptic maintenance |
Receptor Structure and Signaling
The tropomyosin receptor kinase (Trk) family (TrkA, TrkB, TrkC) consists of transmembrane receptors with extracellular ligand-binding domains, transmembrane regions, and intracellular tyrosine kinase domains[@patapoutian2001]. Upon neurotrophin binding:
Dimerization: Neurotrophin binding induces receptor dimerization
Autophosphorylation: Activation of intracellular tyrosine kinase domain
Adaptor recruitment: Shc, PLC-γ, and other adaptors bind phosphorylated tyrosines
Signal cascade activation: Multiple downstream pathways are activatedDownstream Signaling Pathways
Neurotrophin signaling activates several major intracellular cascades:
PI3K/Akt Pathway
The phosphoinositide 3-kinase (PI3K)/Akt pathway is a critical pro-survival signaling cascade activated by neurotrophins[@brunet2001]:
- PI3K activation: p85 adaptor subunit binds phosphorylated Trk receptors
- Akt phosphorylation: PDK1 and mTORC2 phosphorylate Akt at multiple sites
- Pro-survival effects: Akt phosphorylates BAD, inhibits caspase-9, promotes protein synthesis
- Neurodegeneration links: Impaired PI3K/Akt signaling contributes to neuronal death in AD and PD
MAPK/ERK Pathway
The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway mediates neurotrophin effects on synaptic plasticity and neuronal differentiation[@thomas2004]:
- Ras activation: Grb2/SOS complex recruitment activates Ras
- MEK activation: Raf phosphorylates and activates MEK1/2
- ERK activation: MEK phosphorylates ERK1/2
- Nuclear effects: ERK translocates to nucleus to activate transcription factors (CREB, ELK-1)
- Synaptic plasticity: ERK-mediated transcription is critical for long-term memory
PLC-γ Pathway
Phospholipase C-gamma (PLC-γ) activation by neurotrophins generates second messengers[@minichiello2009]:
- PIP2 hydrolysis: PLC-γ hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2)
- DAG and IP3 production: Generates diacylglycerol (DAG) and inositol trisphosphate (IP3)
- Calcium signaling: IP3 triggers calcium release from internal stores
- PKC activation: DAG activates protein kinase C (PKC)
- Synaptic function: PLC-γ signaling modulates synaptic transmission and plasticity
p75NTR Receptor
The p75 neurotrophin receptor (p75NTR, NTR) is a pan-neurotrophin receptor that modulates Trk signaling and can mediate apoptosis in the absence of Trk activation[@rabinovsky2004]:
- Ligand binding: Binds all neurotrophins with low affinity
- Coreceptor requirements: Requires sortilin for pro-neurotrophin signaling
- Apoptotic signaling: Pro-neurotrophin binding triggers caspase activation and neuronal death
- Trk modulation: p75NTR can enhance or inhibit Trk signaling depending on context
Neurotrophin Signaling in Alzheimer's Disease
BDNF and AD Pathogenesis
BDNF signaling is profoundly altered in Alzheimer's disease, contributing to synaptic dysfunction, cognitive decline, and neuronal loss[@mattson2004]:
Reduced BDNF Expression
- Transcriptional downregulation: BDNF mRNA is reduced in AD hippocampus and cortex
- Promoter methylation: Epigenetic silencing of BDNF gene in AD brain
- Activity-dependent deficits: Impaired activity-dependent BDNF release
- Correlation with cognition: BDNF levels correlate with MMSE scores and cognitive function
TrkB Signaling Impairment
- TrkB reduction: TrkB receptor expression is decreased in AD brain
- Signaling cascade disruption: Impaired PI3K/Akt and MAPK/ERK signaling
- Synaptic dysfunction: Reduced TrkB signaling contributes to synaptic loss
- Amyloid effects: Aβ oligomers interfere with TrkB signaling
Amyloid-Beta Effects on Neurotrophin Signaling
Aβ pathology directly interferes with neurotrophin signaling[@dorsey2006]:
- TrkB/Aβ interaction: Aβ oligomers bind to TrkB and block BDNF binding
- Receptor internalization: Aβ promotes aberrant TrkB internalization
- Signal disruption: Aβ impairs downstream PI3K/Akt and MAPK signaling
- Synaptic毒性: Aβ-induced synaptic toxicity is exacerbated by BDNF signaling deficits
Tau Pathology and Neurotrophin Signaling
Tau pathology affects neurotrophin signaling through multiple mechanisms:
- TrkB mislocalization: Tau pathology disrupts TrkB trafficking
- Axonal transport defects: Impaired BDNF transport in tau-bearing neurons
- Synaptic dysfunction: Tau-induced synaptic loss affects neurotrophin-responsive synapses
Therapeutic Strategies for AD
BDNF Delivery Approaches
Multiple strategies to enhance BDNF signaling are being developed for AD[@nagahara2011]:
- Recombinant BDNF: Intravenous or intracerebral BDNF administration
- Gene therapy: AAV-mediated BDNF delivery to brain regions
- Cell therapy: Stem cell-based BDNF delivery
- Small molecules: TrkB agonists in development
TrkB Agonists
Small molecule TrkB agonists represent a promising therapeutic approach[@liu2010]:
| Compound | Stage | Mechanism |
|----------|-------|-----------|
| 7,8-DHF | Preclinical | TrkB agonist, blood-brain barrier permeable |
| BDNF mimetics | Preclinical | Peptide analogs of BDNF active domain |
| TrkB-selective antibodies | Preclinical | Agonistic antibodies targeting TrkB |
Exercise and Environmental Enrichment
Non-pharmacological approaches to enhance neurotrophin signaling[@cotman2007]:
- Aerobic exercise: Increases BDNF expression in hippocampus
- Environmental enrichment: Enhanced BDNF and synaptic plasticity
- Dietary interventions: Omega-3 fatty acids and flavonoids increase BDNF
Neurotrophin Signaling in Parkinson's Disease
BDNF and PD Pathogenesis
BDNF signaling is critical for dopaminergic neuron survival and function, and its dysfunction contributes to PD pathogenesis[@murer2001]:
Nigrostriatal BDNF Deficiency
- Reduced BDNF in substantia nigra: Markedly decreased BDNF in PD substantia nigra
- Ventral tegmental area preservation: Relative sparing of VTA BDNF correlates with less severe motor symptoms
- Activity-dependent deficits: Impaired activity-dependent BDNF release from remaining neurons
- Progressive degeneration: BDNF deficiency accelerates dopaminergic neuron loss
TrkB Signaling Abnormalities
- TrkB downregulation: Reduced TrkB expression in PD nigra
- Impaired downstream signaling: Disrupted PI3K/Akt and MAPK/ERK cascades
- Vulnerability mechanisms: Decreased pro-survival signaling increases neuronal vulnerability
Alpha-Synuclein Effects on Neurotrophin Signaling
- Direct interaction: Alpha-synuclein aggregates interfere with TrkB signaling
- Transport disruption: Impaired axonal transport of BDNF
- Synaptic dysfunction: Loss of BDNF-mediated synaptic maintenance
Therapeutic Strategies for PD
BDNF-Based Therapies
- Gene therapy: AAV-BDNF delivery to striatum and substantia nigra
- Protein delivery: Recombinant BDNF or BDNF mimetics
- Cell replacement: Stem cell-derived dopamine neurons with enhanced BDNF expression
TrkB Modulation
- Agonist development: TrkB agonists to enhance dopaminergic neuron survival
- Allosteric modulators: Positive allosteric modulators of TrkB signaling
Neurotrophin Signaling in Amyotrophic Lateral Sclerosis
Neurotrophin Deficiency in ALS
Motor neurons are particularly dependent on neurotrophin signaling for survival and maintenance[@henderson1996]:
BDNF and Motor Neuron Survival
- Essential for motor neurons: BDNF supports motor neuron survival in development and adulthood
- Axonal maintenance: BDNF signaling maintains axonal integrity
- Neuromuscular junction: BDNF is critical for NMJ formation and maintenance
- ALS-related deficits: BDNF levels are reduced in ALS spinal cord and muscle
Impaired Signaling in ALS
- TrkB downregulation: Reduced TrkB expression in ALS motor neurons
- p75NTR alterations: Changed p75NTR expression affects survival signaling
- Signal transduction defects: Impaired PI3K/Akt signaling in ALS models
Neurotrophin Therapy in ALS
Clinical trials have tested neurotrophin-based therapies for ALS[@bdnf2002]:
- BDNF delivery: Intramuscular and intrathecal BDNF showed limited efficacy
- NT-3 trials: NT-3 delivery toALS patients
- TrkB agonists: Small molecule TrkB agonists in development
- Combination approaches: Neurotrophin delivery with other neuroprotective factors
Non-Motor Neuron Effects
Neurotrophin signaling affects multiple cell types relevant to ALS:
- Astrocytes: Astrocyte neurotrophin production supports motor neurons
- Microglia: Neurotrophin signaling modulates neuroinflammation
- Muscle: Muscle-derived BDNF is important for NMJ integrity
Neurotrophin Signaling in Huntington's Disease
BDNF Dysregulation in HD
Huntington's disease is characterized by profound BDNF deficiency that contributes to striatal and cortical degeneration[@zuccato2009]:
Genetic Mechanisms
- Transcriptional dysregulation: Mutant huntingtin impairs BDNF transcription
- Transport deficits: Impaired axonal transport of BDNF from cortex to striatum
- Reduced cortical BDNF: Cortical BDNF production is reduced in HD
- Striatal uptake: Impaired striatal uptake of BDNF
Signaling Abnormalities
- TrkB signaling defects: Impaired TrkB downstream signaling in HD
- PI3K/Akt disruption: Reduced pro-survival signaling
- Synaptic dysfunction: Loss of BDNF-mediated synaptic maintenance
- Energy metabolism: BDNF signaling interacts with mitochondrial function
Therapeutic Approaches
BDNF Enhancement Strategies
- Gene therapy: AAV-BDNF delivery to striatum
- TrkB agonists: Pharmacological TrkB activation
- Exercise: Voluntary exercise increases BDNF in HD models
Huntingtin Modification
- Transcriptional regulators: Modulating REST and other transcriptional regulators
- BDNF promoter targeting: Epigenetic approaches to enhance BDNF transcription
Neurotrophin Signaling in Other Neurodegenerative Diseases
Multiple Sclerosis
Neurotrophin signaling has complex roles in demyelination and remyelination[@frost2008]:
- NGF and oligodendrocytes: NGF supports oligodendrocyte precursor survival
- BDNF in remyelination: BDNF promotes remyelination in animal models
- Clinical trials: NGF and BDNF delivery approaches in MS
Frontotemporal Dementia
FTD involves neurotrophin signaling alterations[@chenplotkin2010]:
- Progranulin connections: Progranulin mutations affect neurotrophin signaling
- BDNF deficits: Reduced BDNF in FTD brain
- TDP-43 pathology: TDP-43 affects neurotrophin expression
Diabetic Neuropathy
Peripheral neuropathy in diabetes involves neurotrophin deficits[@anand1996]:
- NGF deficiency: Reduced NGF in diabetic neuropathy
- Target-derived support: Loss of neurotrophin support leads to axonal degeneration
- Therapeutic approaches: NGF and BDNF delivery in clinical trials
Neuroinflammation and Neurotrophin Signaling
Immune System Interactions
Neurotrophin signaling bidirectionally interacts with neuroinflammatory processes[@venesio2006]:
Neurotrophin Effects on Immune Cells
- Microglial modulation: BDNF affects microglial activation state
- Anti-inflammatory effects: BDNF can reduce pro-inflammatory cytokine production
- T cell modulation: Neurotrophins modulate adaptive immune responses
Inflammation Effects on Neurotrophins
- Pro-inflammatory cytokines: TNF-α, IL-1β, and IL-6 reduce BDNF expression
- Microglial BDNF: Activated microglia can produce BDNF
- Dysregulated signaling: Inflammation impairs neurotrophin signaling cascades
Therapeutic Implications
- Combination approaches: Anti-inflammatory + neurotrophin-enhancing strategies
- Targeting neuroinflammation: Reducing inflammation to restore neurotrophin signaling
- Immune modulation: Modulating immune cells to enhance neurotrophin production
Sex Differences in Neurotrophin Signaling
Estrogen Interactions
Estrogen modulates neurotrophin signaling in significant ways[@spencer2000]:
- BDNF regulation: Estrogen increases BDNF expression
- TrkB modulation: Estrogen affects TrkB expression and signaling
- Synaptic plasticity: Estrogen-BDNF interactions mediate synaptic effects
- Neuroprotection: Combined estrogen/BDNF signaling is neuroprotective
Implications for Disease
- AD sex differences: Female susceptibility may involve neurotrophin signaling
- PD sex differences: Men exhibit greater dopaminergic vulnerability
- Therapeutic considerations: Sex-specific approaches may be warranted
Biomarkers and Diagnostic Applications
Peripheral BDNF Measurements
Blood-based BDNF measurements are being explored as biomarkers[@zuccato2007]:
- Serum vs. plasma: Different compartments provide different information
- Disease correlations: BDNF levels correlate with disease severity
- Treatment monitoring: BDNF changes may reflect treatment response
- Limitations: Peripheral measurements may not reflect brain BDNF
CSF Neurotrophin Measurements
Cerebrospinal fluid offers closer access to CNS neurotrophins[@niere2008]:
- BDNF in CSF: Measurable BDNF in human CSF
- Diagnostic value: Altered CSF BDNF in AD, PD, and other diseases
- Correlation with brain: CSF BDNF may better reflect CNS status
Genetic Markers
BDNF gene polymorphisms affect disease risk and treatment response[@pivocar2012]:
- Val66Met polymorphism: Common variant affects BDNF trafficking and function
- Disease associations: Val66Met influences AD and PD risk
- Treatment response: Polymorphism affects response to neurotrophin-based therapies
Therapeutic Development Pipeline
Small Molecule TrkB Agonists
Several TrkB-targeting small molecules are in development[@jang2010]:
| Compound | Development Stage | Notes |
|----------|-------------------|-------|
| 7,8-DHF | Preclinical | Natural product, BBB permeable |
| TLT-Y-1 | Preclinical | Selective TrkB agonist |
| LM22A-4 | Preclinical | Small molecule BDNF mimetic |
Peptide-Based Therapies
Peptide approaches offer improved specificity[@longo2004]:
- BDNF-derived peptides: Active domains of BDNF
- TrkB-binding peptides: Designed peptides targeting TrkB
- Cell-penetrating peptides: Enhanced delivery to neurons
Gene Therapy Approaches
Viral vectors enable sustained neurotrophin expression[@klein2010]:
- AAV-BDNF: Adeno-associated virus-mediated BDNF delivery
- Safety considerations: Controlling expression levels is critical
- Clinical trials: Ongoing gene therapy approaches
Cell-Based Therapies
Cellular approaches provide local neurotrophin production[@martinez2012]:
- Stem cell delivery: Stem cells engineered to secrete BDNF
- Encapsulated cells: Immobilized cells releasing neurotrophins
- Combination approaches: Cells with enhanced survival and neurotrophin production
Drug Repurposing
Existing drugs with neurotrophin-enhancing effects are being explored[@ventriglia2009]:
- Antidepressants: SSRIs increase BDNF expression
- Statins: Some statins enhance BDNF signaling
- Anti-diabetic drugs: GLP-1 agonists affect neurotrophin signaling
Mechanisms of Neurotrophin-Based Therapies
Neurotrophin therapies exert neuroprotective effects through multiple mechanisms[@almeida2005]:
- Anti-apoptotic signaling: PI3K/Akt-mediated inhibition of caspases
- Metabolic support: Enhanced glucose metabolism and mitochondrial function
- Calcium homeostasis: Stabilization of calcium handling
- Oxidative stress protection: Enhanced antioxidant defenses
Enhancing Synaptic Plasticity
Neurotrophins modulate synaptic function and plasticity[@lu2008]:
- Synapse formation: BDNF promotes excitatory synapse formation
- LTP enhancement: BDNF is required for long-term potentiation
- Dendritic spine morphology: BDNF affects spine shape and density
- Neurotransmitter release: Modulates presynaptic function
Modulating Neuroinflammation
Neurotrophins have immunomodulatory properties[@gomes2012]:
- Microglial phenotype: Shifting microglia toward anti-inflammatory state
- Cytokine regulation: Reducing pro-inflammatory cytokine production
- T cell modulation: Effects on adaptive immunity
Supporting Neurogenesis
Neurotrophin signaling promotes neural stem cell function[@sohur2011]:
- Proliferation: BDNF stimulates neural progenitor proliferation
- Differentiation: Directing neuronal differentiation
- Survival: Supporting newborn neuron survival
- Integration: Enhancing functional integration
Challenges and Future Directions
Delivery Challenges
Effective neurotrophin delivery to the CNS remains challenging[@pardridge2007]:
- Blood-brain barrier: Limited BBB penetration
- Protein stability: Short half-life of neurotrophins
- Receptor specificity: Achieving selective TrkB activation
- Distribution: Achieving uniform brain distribution
Combination Therapies
Future approaches will likely combine neurotrophin enhancement with other strategies[@thoenen2002]:
- Neurotrophins + anti-amyloid: Combined approaches for AD
- Neurotrophins + neuroinflammation: Targeting multiple pathways
- Neurotrophins + cell therapy: Combined cell replacement and trophic support
- Personalized approaches: Genetic and biomarker-guided therapy selection
Biomarker Development
Better biomarkers will enable improved clinical development[@konrath2012]:
- Target engagement markers: Demonstrating TrkB activation
- Response biomarkers: Predicting treatment response
- Disease progression markers: Monitoring disease modification
- Sex-specific markers: Accounting for sex differences
Normal Aging
Neurotrophin signaling undergoes characteristic changes with normal aging[@mattson2010]:
BDNFDecline
- Hippocampal reduction: BDNF levels decline with age in hippocampus
- Cortical changes: Age-related BDNF reduction in cortex
- Activity-dependent deficits: Impaired activity-induced BDNF release
- Functional consequences: Contributes to age-related cognitive decline
Receptor Changes
- TrkB alterations: Age-related changes in TrkB expression and signaling
- Signaling cascade impairment: Reduced PI3K/Akt and MAPK/ERK signaling
- Synaptic effects: Decreased neurotrophin support for synapses
- Cognitive implications: Contributes to memory impairment in aging
Neurotrophin and Brain Reserve
Higher baseline neurotrophin levels are associated with greater brain reserve[@buchman2012]:
- Cognitive reserve: BDNF supports cognitive reserve capacity
- Neuroplasticity: Enhanced capacity for neural compensation
- Protection against pathology: May provide resilience to pathology
- Successful aging: High BDNF correlates with successful cognitive aging
Neurotrophin signaling is intimately linked to glucose metabolism[@tonoli2015]:
- BDNF effects on metabolism: BDNF influences glucose uptake and insulin sensitivity
- Metabolic syndrome: Metabolic dysfunction affects neurotrophin signaling
- Insulin signaling: Cross-talk between insulin and TrkB signaling
- Therapeutic implications: Metabolic modulation affects neurotrophin therapy
Ketogenic Diet Effects
Ketogenic diets may influence neurotrophin signaling[@muller2010]:
- BDNF elevation: Ketogenic diets increase BDNF expression
- Mechanism studies: Ketone bodies may directly affect TrkB signaling
- Therapeutic potential: Ketogenic approaches for neurodegenerative diseases
- Combined strategies: Ketogenic diet plus neurotrophin enhancement
Circadian Regulation of Neurotrophins
Diurnal BDNF Variation
BDNF shows circadian regulation in the brain[@schmidt2015]:
- Daily patterns: Circadian variation in BDNF expression
- Light effects: Light exposure affects BDNF levels
- Sleep relationships: Sleep stages correlate with BDNF fluctuations
- Disease implications: Disrupted circadian BDNF in neurodegeneration
Sleep and Neurotrophin Signaling
Sleep is critical for neurotrophin-mediated processes[@born2010]:
- REM sleep: BDNF is released during REM sleep
- Memory consolidation: Sleep-dependent memory consolidation involves BDNF
- Sleep deprivation: Sleep loss reduces BDNF expression
- Therapeutic potential: Sleep optimization as neurotrophin strategy
Environmental Enrichment Effects
Enrichment Paradigms
Environmental enrichment enhances neurotrophin signaling[@van2007]:
- Complex environments: Enriched housing increases BDNF
- Social interaction: Social enrichment affects BDNF expression
- Sensory stimulation: Sensory enrichment increases neurotrophins
- Mechanisms: Epigenetic and transcriptional regulation
Translational Applications
Enrichment approaches are being translated to human applications[@kempermann2010]:
- Cognitive training: Cognitive stimulation increases peripheral BDNF
- Physical activity: Combined physical and cognitive activity optimal
- Social engagement: Social activities enhance neurotrophins
- Multimodal approaches: Combining multiple enrichment strategies
Emerging Research Directions
Epigenetic Modulation
Epigenetic approaches to enhance neurotrophin expression are emerging[@fischer2007]:
- BDNF promoter regulation: Targeting BDNF gene methylation
- Histone modifications: HDAC inhibitors increase BDNF expression
- Non-coding RNAs: miRNAs targeting BDNF
- CRISPR approaches: Gene editing to enhance BDNF expression
Single-Cell Analysis
Single-cell approaches are revealing cell-type-specific neurotrophin biology[@saunders2018]:
- Neuronal heterogeneity: Different neuron types have distinct neurotrophin requirements
- Astrocyte roles: Astrocyte-derived neurotrophins
- Microglial interactions: Cell-type-specific signaling
- Therapeutic targeting: Cell-type-specific approaches
Optogenetic Approaches
Optogenetics enables precise neurotrophin pathway manipulation[@leong2019]:
- TrkB activation: Optogenetic TrkB activation
- Circuit-specific effects: Targeting specific neural circuits
- Temporal control: Precise temporal manipulation of signaling
- Research tools: Understanding neurotrophin function
Nanotechnology
Nanotechnology approaches are being developed for neurotrophin delivery[@gultekin2019]:
- Nanoparticle encapsulation: Protecting neurotrophins from degradation
- Targeted delivery: CNS-specific targeting
- Controlled release: Sustained neurotrophin release
- Combination nanocarriers: Multiple therapeutic payloads
Brain-Computer Interfaces
BCI technology may enable novel neurotrophin modulation approaches[@ramirezzamora2020]:
- Neural activity modulation: Using neural signals to guide therapy
- Closed-loop systems: Responsive neurotrophin delivery
- Integration with brain stimulation: Combined approaches
- Monitoring and adjustment: Real-time treatment optimization
See Also
- [BDNF Gene](/genes/bdnf)
- [BDNF Protein](/proteins/bdnf-protein)
- [Alzheimer's Disease Mechanisms](/diseases/alzheimers-disease)
- [Parkinson's Disease Mechanisms](/diseases/parkinsons-disease)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Huntington's Disease](diseases/huntingtons)
- [Synaptic Plasticity Mechanisms](/mechanisms/synaptic-plasticity)
- [Neurotrophin Signaling Pathway](/mechanisms/neurotrophin-signaling-pathway)
References
[Unknown, Levi-Montalcini, The nerve growth factor (1987) (1987)](https://pubmed.ncbi.nlm.nih.gov/3301455/)
[Unknown, Huang & Reichardt, Neurotrophins (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11252042/)
[Unknown, Patapoutian & Reichardt, Trk receptors (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11410274/)
[Brunet et al., PI3K/Akt signaling in neuroprotection (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11278696/)
[Unknown, Thomas & Huganir, MAPK signaling in synaptic plasticity (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15270757/)
[Unknown, Minichiello, TrkB signaling mechanisms (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19776747/)
[Rabinovsky et al., p75NTR in neurodegeneration (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15068656/)
[Mattson et al., BDNF in AD (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/14749444/)
[Dorsey et al., Aβ effects on TrkB signaling (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16467539/)
[Unknown, Nagahara & Tuszynski, BDNF gene therapy for AD (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/22025051/)
[Liu et al., TrkB agonists for neurodegeneration (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20655058/)
[Cotman et al., Exercise and BDNF (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17827791/)
[Murer et al., BDNF in PD (2001) (2001)](https://pubmed.ncbi.nlm.nih.gov/11240081/)
[Henderson et al., Neurotrophins in ALS (1996) (1996)](https://pubmed.ncbi.nlm.nih.gov/8788438/)
[Unknown, BDNF trials in ALS (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/12428759/)
[Unknown, Zuccato & Cattaneo, BDNF in HD (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19687015/)
[Frost et al., Neurotrophins in MS (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18434189/)
[Chen-Plotkin et al., Neurotrophins in FTD (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20628650/)
[Anand et al., Neurotrophins in diabetic neuropathy (1996) (1996)](https://pubmed.ncbi.nlm.nih.gov/8786366/)
[Venesio et al., Neurotrophins and neuroinflammation (2006) (2006)](https://pubmed.ncbi.nlm.nih.gov/16466944/)
[Spencer et al., Estrogen and BDNF interactions (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10657678/)
[Unknown, Zuccato & Cattaneo, Peripheral BDNF as biomarker (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17656450/)
[Niere et al., CSF neurotrophins (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18660451/)
[Pivocar et al., BDNF Val66Met polymorphism (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22025197/)
[Jang et al., 7,8-DHF as TrkB agonist (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20127938/)
[Unknown, Longo & Massa, Small molecule neurotrophin mimetics (2004) (2004)](https://pubmed.ncbi.nlm.nih.gov/15027865/)
[Klein et al., AAV-BDNF gene therapy (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20053747/)
[Martinez et al., Stem cell BDNF delivery (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22797065/)
[Ventriglia et al., SSRIs and BDNF in AD (2009) (2009)](https://pubmed.ncbi.nlm.nih.gov/19268454/)
[Almeida et al., Neurotrophin anti-apoptotic mechanisms (2005) (2005)](https://pubmed.ncbi.nlm.nih.gov/16039575/)
[Lu et al., BDNF and synaptic plasticity (2008) (2008)](https://pubmed.ncbi.nlm.nih.gov/18660958/)
[Gomes et al., Neurotrophin immunomodulation (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22341541/)
[Sohur et al., BDNF and neurogenesis (2011) (2011)](https://pubmed.ncbi.nlm.nih.gov/21876458/)
[Unknown, Pardridge, Neurotrophin delivery challenges (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17959034/)
[Unknown, Thoenen & Sendtner, Neurotrophin combination therapies (2002) (2002)](https://pubmed.ncbi.nlm.nih.gov/12446739/)
[Konrath et al., Neurotrophin biomarker development (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22895899/)
[Unknown, Mattson, BDNF and aging (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20452142/)
[Buchman et al., BDNF and cognitive reserve (2012) (2012)](https://pubmed.ncbi.nlm.nih.gov/22784278/)
[Tonoli et al., BDNF and metabolism (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26553442/)
[Muller et al., Ketogenic diet and BDNF (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20463752/)
[Unknown, Schmidt, Circadian BDNF (2015) (2015)](https://pubmed.ncbi.nlm.nih.gov/26036503/)
[Unknown, Born, Sleep and memory (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20061393/)
[van Praag et al., Environmental enrichment (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/18052805/)
[Unknown, Kempermann, Human enrichment (2010) (2010)](https://pubmed.ncbi.nlm.nih.gov/20158745/)
[Fischer et al., Epigenetic BDNF modulation (2007) (2007)](https://pubmed.ncbi.nlm.nih.gov/17629460/)
[Unknown, Saunders & Macosko, Single-cell neurotrophin biology (2018) (2018)](https://pubmed.ncbi.nlm.nih.gov/29988126/)
[Leong et al., Optogenetic TrkB (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31158965/)
[Gultekin et al., Nanotechnology for neurotrophin delivery (2019) (2019)](https://pubmed.ncbi.nlm.nih.gov/31127834/)
[Ramirez-Zamora et al., Brain-computer interfaces (2020) (2020)](https://pubmed.ncbi.nlm.nih.gov/32147823/)