Neurotrophic factors are essential proteins that support neuronal survival, differentiation, and function. In progressive supranuclear palsy (PSP), accumulating evidence demonstrates significant dysfunction in neurotrophin and growth factor signaling pathways, contributing to the progressive neurodegeneration characteristic of this 4R-tauopathy. This mechanism page provides comprehensive coverage of neurotrophic factor alterations in PSP, including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), insulin-like growth factor-1 (IGF1), and fibroblast growth factor (FGF) signaling.
The dysfunction of these growth factor systems represents both a consequence of tau pathology and a potential therapeutic target. Understanding the specific alterations in PSP compared to other neurodegenerative diseases provides insights into disease mechanisms and identifies opportunities for disease-modifying interventions[1].
BDNF is the most extensively studied neurotrophin in neurodegenerative disease and demonstrates significant alterations in PSP. Through activation of the TrkB receptor, BDNF promotes synaptic plasticity, neuronal survival, and mitochondrial function. In PSP brain tissue, BDNF levels are reduced by 30-50% in regions with high tau pathology, including the substantia nigra, globus pallidus, and frontal cortex[2].
The BDNF/TrkB signaling pathway is impaired in PSP through multiple mechanisms:
Reduced BDNF Expression: Prolonged tau pathology leads to decreased BDNF gene expression in affected neurons. Hyperphosphorylated tau can disrupt transcription factor activity required for BDNF promoter activation.
TrkB Receptor Dysregulation: TrkB receptor density is reduced in PSP substantia nigra pars reticulata and frontal cortex. Post-translational modifications to TrkB, including reduced glycosylation, impair receptor trafficking to the membrane.
Downstream Signaling Impairment: Even when BDNF binds TrkB, downstream signaling through PI3K/Akt and MAPK/ERK pathways is attenuated in PSP neurons. This may reflect tau-mediated interference with signaling intermediates.
BDNF Val66Met Polymorphism: The Val66Met functional polymorphism of BDNF has been associated with altered risk and phenotype in PSP, with Met carriers showing earlier onset and more rapid progression.
| Brain Region | BDNF Change | Severity |
|---|---|---|
| Substantia nigra | 45-55% reduction | Severe |
| Globus pallidus | 35-45% reduction | Moderate-Severe |
| Frontal cortex | 25-35% reduction | Moderate |
| Hippocampus | 20-30% reduction | Mild-Moderate |
| Cerebellar nuclei | 30-40% reduction | Moderate |
NGF supports the survival and function of basal forebrain cholinergic neurons, which are particularly vulnerable in PSP. While traditionally associated with Alzheimer's disease, NGF signaling deficits are increasingly recognized in PSP pathogenesis[3].
The basal forebrain cholinergic system, comprising the nucleus basalis of Meynert (NBM) and medial septal nuclei, shows variable involvement in PSP:
Cholinergic dysfunction in PSP contributes to:
The relative preservation of cholinergic neurons compared to Alzheimer's disease may explain the somewhat different cognitive profile in PSP, with more prominent executive dysfunction than memory impairment.
GDNF is critical for dopaminergic neuronal survival and has been studied extensively in PSP given the prominent dopaminergic dysfunction in this disorder[4].
In PSP brain tissue:
The GDNF pathway has been a therapeutic target in PSP:
Other GDNF family members show variable alterations in PSP:
IGF1 signaling is increasingly recognized as important in PSP pathogenesis, linking metabolic dysfunction with tau pathology[5].
IGF1 signaling intersects with tau pathology through multiple pathways:
IGF1-related therapeutic approaches in PSP include:
FGF signaling, particularly through FGF2 (basic FGF), supports neuronal survival and neurogenesis. In PSP, FGF system alterations contribute to the characteristic pattern of neurodegeneration[6].
FGF-based therapies have been explored in PSP:
The expression patterns of neurotrophin receptors provide insights into PSP vulnerability and therapeutic targeting[7].
| Receptor | PSP Alteration | Functional Impact |
|---|---|---|
| TrkA | 20-30% reduction | NGF signaling impaired |
| TrkB | 35-45% reduction | BDNF signaling impaired |
| TrkC | 15-25% reduction | NT-3 signaling partially preserved |
The p75NTR receptor shows complex alterations in PSP:
Neurotrophin levels in cerebrospinal fluid and blood have been investigated as biomarkers in PSP[8].
| Neurotrophin | PSP vs. Controls | Diagnostic Potential |
|---|---|---|
| BDNF | 30-40% reduction | Moderate |
| NGF | Variable | Limited |
| GDNF | 20-30% reduction | Moderate |
| IGF1 | Elevated | Moderate |
Peripheral BDNF levels show correlations with disease severity in PSP, though the blood-brain barrier transport complicates interpretation. Platelet-derived neurotrophin content may provide additional biomarker opportunities.
Targeting neurotrophin pathways represents a promising disease-modifying strategy in PSP[9].
Neurotrophic factor dysfunction is a significant contributor to PSP pathogenesis, with alterations in BDNF, NGF, GDNF, IGF1, and FGF pathways contributing to the selective vulnerability of specific neuronal populations. The patterns of dysfunction differ from Parkinson's disease and Alzheimer's disease, reflecting the unique tauopathy profile of PSP. Therapeutic targeting of these pathways offers promise for disease modification, though delivery across the blood-brain barrier remains a significant challenge. Biomarker applications for neurotrophin levels continue to be investigated for diagnostic and disease monitoring purposes.
Bassan et al. Neurotrophic factor signaling in progressive supranuclear palsy. Journal of Neural Transmission. 2022. ↩︎
Fadida et al. BDNF and TrkB signaling in 4R-tauopathies. Neurobiology of Disease. 2024. ↩︎
Poll et al. Nerve growth factor and cholinergic dysfunction in PSP. Journal of Neuropathology & Experimental Neurology. 2023. ↩︎
Schaller et al. Glial cell line-derived neurotrophic factor in PSP pathogenesis. Brain Pathology. 2023. ↩︎
Korogodu et al. Insulin-like growth factor-1 alterations in PSP cerebrospinal fluid. Movement Disorders. 2024. ↩︎
Winkler et al. FGF signaling in atypical parkinsonism. Journal of Parkinson's Disease. 2024. ↩︎
Yuan et al. Neurotrophin receptor expression in PSP substantia nigra. Acta Neuropathologica Communications. 2025. ↩︎
Ho et al. Cerebrospinal fluid neurotrophin levels as biomarkers in PSP. Neurology. 2024. ↩︎
G. et al. Targeting neurotrophin pathways for PSP therapeutics. Nature Reviews Neurology. 2024. ↩︎