| Growth Factor Signaling in 4R-Tauopathies | |
|---|---|
| Diseases Covered | PSP, CBD, AGD, GGT, FTDP-17 |
| Growth Factors | IGF1, BDNF, NGF, FGF, GDNF, NT-3, NT-4 |
| Key Pathways | PI3K/Akt, MAPK/ERK, mTOR, PLCγ |
| Receptors | TrkA, TrkB, TrkC, FGFR, IGF-1R, RET |
Growth factor signaling is a critical pathway network that regulates neuronal survival, synaptic plasticity, and trophic support in the central nervous system. In 4R-tauopathies—including Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and Frontotemporal Dementia with Parkinsonism linked to chromosome 17 (FTDP-17)—dysregulation of growth factor signaling contributes to disease pathogenesis through multiple mechanisms[1][2].
The 4R-tauopathies share common features including:
Growth factor signaling provides essential neurotrophic support to neurons affected in these disorders. Understanding the shared and disease-specific alterations in this signaling network offers therapeutic opportunities.
The neurotrophin family includes Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4). These proteins signal through Trk (tropomyosin receptor kinase) receptors and p75^NTR[3]:
| Neurotrophin | Primary Receptor | Key Functions |
|---|---|---|
| NGF | TrkA | Cholinergic neuron survival, memory |
| BDNF | TrkB | Synaptic plasticity, cognition |
| NT-3 | TrkC | Motor neuron support |
| NT-4 | TrkB | Synaptic maintenance |
NGF supports basal forebrain cholinergic neurons that degenerate in PSP and CBD. BDNF through TrkB signaling is critical for synaptic function and is impaired in several 4R-tauopathies[4][5].
IGF1 (Insulin-like Growth Factor 1) signals through IGF-1R and activates PI3K/Akt and MAPK pathways. IGF1 has neuroprotective properties and modifies tau pathology[6][7]:
IGF1 is particularly relevant in GGT where oligodendroglial pathology may affect IGF signaling[8].
The FGF family includes multiple members with neurotrophic properties:
FGF signaling through FGFR (Fibroblast Growth Factor Receptor) activates both MAPK/ERK and PI3K/Akt pathways[11].
GDNF (Glial Cell Line-Derived Neurotrophic Factor) and related proteins signal through RET receptor complex:
GDNF family signaling is important for dopaminergic neurons affected in PSP[12].
The PI3K/Akt pathway is a central mediator of growth factor signaling:
PI3K/Akt dysregulation contributes to tau hyperphosphorylation and synaptic dysfunction in 4R-tauopathies[7:1].
The MAPK/ERK pathway mediates growth factor effects on neuronal plasticity:
The mTOR pathway integrates growth factor and nutrient signals:
Dysregulated mTOR signaling contributes to impaired autophagy in 4R-tauopathies.
In PSP, growth factor alterations include:
NGF and cholinergic signaling:
BDNF signaling:
IGF1:
CBD involves multiple growth factor systems:
GDNF signaling:
FGF signaling:
BDNF:
AGD shows growth factor changes:
FGF expression:
Neurotrophin signaling:
GGT shows unique growth factor profiles:
IGF1 signaling:
FGF signaling:
FTDP-17 with MAPT mutations shows:
BDNF dysfunction:
Neurotrophin signaling:
| Growth Factor | PSP | CBD | AGD | GGT | FTDP-17 |
|---|---|---|---|---|---|
| NGF/Choline | ↓↓ | ↓↓ | ↓ | ↓ | ↓ |
| BDNF/TrkB | ↓↓ | ↓↓ | ↓ | ↓↓ | ↓↓ |
| IGF1 | ↓ | ↓ | ↓ | ↓↓ | ↓ |
| FGF2 | ↓ | ↓ | ↓↓ | ↓ | ↓ |
| GDNF | ↓ | ↓↓ | ↓ | ↓ | ↓ |
↑ = Increased, ↓ = Decreased, ↓↓ = Severely decreased
All 4R-tauopathies show:
BDNF delivery:
NGF therapy:
Small molecule approaches:
Receptor agonists:
mTOR modulation:
PI3K/Akt modulation:
Growth factor levels in blood:
Cerebrospinal fluid measurements:
Growth factor signaling is fundamentally altered in all 4R-tauopathies, with both shared and disease-specific mechanisms. The PI3K/Akt, MAPK/ERK, and mTOR pathways represent common therapeutic targets. BDNF/TrkB and IGF1 signaling are particularly affected across diseases.
Understanding the nuanced differences between PSP, CBD, AGD, GGT, and FTDP-17 enables precision therapeutic approaches. Current strategies include neurotrophin delivery, small molecule agonists, and pathway modulators.
Nerve growth factor in progressive supranuclear palsy. 2023. ↩︎
FGF20 is a selective dopaminergic neurotrophic factor. 2021. ↩︎
GDNF family ligands and RET signaling in the brain. 2020. ↩︎
Selaginella polyphenols enhance neurotrophin expression. 2023. ↩︎
Rosiglitazone promotes neuroprotection via PPARgamma in tauopathies. 2022. ↩︎