Neuropeptide and GPCR Signaling in 4R-Tauopathies

Neuropeptide and GPCR Signaling in 4R-Tauopathies

Introduction

The four-repeat (4R) tauopathies represent a group of neurodegenerative disorders characterized by the preferential accumulation of 4R tau isoforms. This page examines the role of neuropeptide signaling and G protein-coupled receptor (GPCR) pathways in Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and FTDP-17 (MAPT mutations). Understanding neuropeptide dysregulation provides insights into disease mechanisms and identifies potential therapeutic targets[@bjorklund2020].

```mermaid
flowchart TD
subgraph NeuropeptideSystems
NPY["Neuropeptide Y"]
SP["Substance P"]
ORX["Orexin/Hypocretin"]
GHR["Ghrelin"]
MLT["Melatonin"]
end

subgraph GPCRSystems
NPYR["NPY receptors Y1,Y2,Y5"]
NK1R["NK1 receptor"]
OX1R["Orexin receptors OX1R,OX2R"]
GHSR["GHSR 1a"]
MTR["Melatonin receptors"]
end

subgraph Signaling
Gi["Gi/o -> -cAMP"]
Gq["Gq -> PLC/IP3"]
Gs["Gs -> +cAMP"]
Arrestin["beta-arrestin pathways"]
end

subgraph Diseases4R
PSP["Progressive Supranuclear Palsy"]
CBD["Corticobasal Degeneration"]
AGD["Argyrophilic Grain Disease"]
GGT["Globular Glial Tauopathy"]
FTDP["FTDP-17"]
end

NPY --> NPYR --> Gi
SP --> NK1R --> Gq
ORX --> OX1R --> Gq
GHR --> GHSR --> Gs
MLT --> MTR --> Gi

Neuropeptide and GPCR Signaling in 4R-Tauopathies

Introduction

The four-repeat (4R) tauopathies represent a group of neurodegenerative disorders characterized by the preferential accumulation of 4R tau isoforms. This page examines the role of neuropeptide signaling and G protein-coupled receptor (GPCR) pathways in Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Argyrophilic Grain Disease (AGD), Globular Glial Tauopathy (GGT), and FTDP-17 (MAPT mutations). Understanding neuropeptide dysregulation provides insights into disease mechanisms and identifies potential therapeutic targets[@bjorklund2020].

Neuropeptide Systems in 4R-Tauopathies

Neuropeptide Y (NPY)

Neuropeptide Y is one of the most abundant neuropeptides in the central nervous system, involved in appetite regulation, stress response, anxiety, and synaptic plasticity[@yuan2025].

Alterations in Each Disease

| Disease | NPY Change | Anatomical Location | Clinical Correlation |
|---------|-----------|-----------------|-------------------|
| PSP | Reduced NPY immunoreactivity | Substantia nigra, globus pallidus | Gait freezing, postural instability |
| CBD | Variable NPY levels | Motor cortex, basal ganglia | Limb rigidity, apraxia |
| AGD | Preserved NPY expression | Hippocampus, amygdala | Mild cognitive impairment |
| GGT | Reduced in white matter | Oligodendrocytes | White matter degeneration |
| FTDP-17 | NPY reduction with MAPT mutations | Frontal cortex | Behavioral variant FTD |

NPY Receptor Signaling

NPY signals through multiple receptor subtypes (Y1, Y2, Y4, Y5), all coupling to Gi/o proteins to inhibit adenylate cyclase and reduce cAMP[@johnson2022]:

• Y1 receptor: Most abundant in cortex and hippocampus; mediates anxiogenic effects
• Y2 receptor: Presynaptic autoinceptor; modulates neurotransmitter release
• Y5 receptor: Hypothalamic; regulates feeding and circadian rhythms

Substance P and the Tachykinin System

Substance P is a member of the tachykinin family involved in pain transmission, neuroinflammation, and Mood regulation[@davis2019].

Alterations in Each Disease

| Disease | Substance P Change | Neuroinflammatory Role |
|---------|---------------------|----------------------|
| PSP | Decreased in substantia nigra | Neuroinflammation contributes to tau pathology |
| CBD | Altered in motor cortex | Associated with cortical degradation |
| AGD | Variable changes | Modest neuroinflammatory response |
| GGT | Reduced in oligodendrocytes | Less studied |
| FTDP-17 | Reduced in frontal cortex | Correlates with behavior changes |

NK1 Receptor Signaling

The NK1 receptor (TACR1) primarily couples to Gq proteins, activating phospholipase C and generating IP3/DAG:

Orexin/Hypocretin System

The orexin system regulates wakefulness, appetite, and reward. Orexin neurons are specifically lost in PSP, contributing to sleep fragmentation[@chen2024][@williams2021].

Alterations in Each Disease

| Disease | Orexin Change | Sleep Phenotype |
|---------|--------------|-----------------|
| PSP | Marked orexin neuron loss | Severe sleep fragmentation, REM behavior disorder |
| CBD | Moderate orexin reduction | Sleep apnea, daytime somnolence |
| AGD | Minimal change | Mild sleep disruption |
| GGT | Variable | Sleep disorders reported |
| FTDP-17 | Variable | Sleep disturbance common |

Orexin Receptor Signaling

Orexin A and orexin B signal through OX1R and OX2R, both coupling primarily to Gq proteins:

Ghrelin and Growth Hormone Secretagogue Receptor

Ghrelin is the "hunger hormone" and exerts neuroprotective effects through the growth hormone secretagogue receptor 1a (GHSR1a)[@smith2024].

Alterations in Each Disease

| Disease | Ghrelin Change | Metabolic Correlation |
|---------|---------------|----------------------|
| PSP | Reduced ghrelin levels | Weight loss, malnutrition |
| CBD | Altered ghrelin signaling | Cachexia common |
| AGD | Variable | Less prominent |
| GGT | Not well studied | May relate to motor-predominant symptoms |
| FTDP-17 | Variable | Appetite changes in bvFTD |

GHSR1a Signaling

GHSR1a is unique among neuropeptide receptors as having high constitutive activity. It signals through multiple pathways:

• Gq pathway: PLC activation leading to IP3/DAG and calcium release
• G_s pathway: cAMP production (constitutive)
• Beta-arrestin pathway: MAPK activation independent of G proteins

Melatonin and Circadian Regulation

Melatonin regulates circadian rhythms and shows alterations in several 4R-tauopathies[@martinez2025].

Alterations in Each Disease

| Disease | Melatonin Change | Circadian Phenotype |
|---------|-----------------|---------------------|
| PSP | Reduced nocturnal melatonin | Sleep fragmentation, sunset sign |
| CBD | Altered melatonin rhythm | Sleep disorders common |
| AGD | Mild reduction | Sleep disruption in pathogenesis |
| GGT | Not well studied | May be affected |
| FTDP-17 | Reduced melatonin | Sleep-wake cycle disruption |

Melatonin Receptor Signaling

MT1 and MT2 melatonin receptors couple primarily to Gi/o proteins:

GPCR Signaling Pathways in Tauopathies

Overview of G Protein Coupling

The neuropeptide receptors in 4R-tauopathies couple to different G protein families with distinct downstream effects[@holmes2023]:

Disease-Specific GPCR Dysregulation

| Disease | Primary GPCR Dysfunction | Therapeutic Target Potential |
|---------|-------------------------|------------------------------|
| PSP | NPY Y1/Y2 deficiency, orexin loss | NPY receptor modulators, orexin agonists |
| CBD | NK1 receptor alterations | NK1 antagonists, neuroinflammation modulators |
| AGD | Preserved neuropeptide signaling | Minimal intervention needed |
| GGT | Ghrelin pathway changes | GHSR1a modulators |
| FTDP-17 | Multiple neuropeptide changes | Combination therapy |

Cross-Disease Comparison

Summary Table: Neuropeptide Alterations

| Neuropeptide | PSP | CBD | AGD | GGT | FTDP-17 |
|-------------|-----|-----|-----|-----|---------|
| NPY | ↓↓ | ↓/↔ | ↔ | ↓ | ↓ |
| Substance P | ↓↓ | ↓ | ↔/↓ | ↓ | ↓ |
| Orexin | ↓↓↓ | ↓↓ | ↔ | ↔ | ↓/↔ |
| Ghrelin | ↓↓ | ↓ | ↔/↓ | ? | ↓ |
| Melatonin | ↓↓ | ↓ | ↓ | ? | ↓ |

Legend: ↓↓ = markedly reduced, ↓ = reduced, ↔ = normal, ? = unknown

Neuropeptide-GPCR Network in 4R-Tauopathies

Therapeutic Implications

Current Therapeutic Approaches

| Target | Approach | Disease | Status |
|--------|----------|---------|--------|
| NPY Y1/Y2 | Agonists | PSP | Preclinical |
| NK1 | Antagonists | CBD | Preclinical |
| Orexin | Agonists | PSP | Investigational |
| GHSR1a | Inverse agonists | PSP, CBD | Preclinical |
| Melatonin | Supplementation | PSP, AGD | Clinical trials |

Emerging Strategies

See Also

• [Neuropeptide Signaling Pathway](/mechanisms/neuropeptide-signaling)
• [GPCR Signaling](/mechanisms/gpcr-signaling)
• [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
• [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
• [Argyrophilic Grain Disease](/diseases/argyrophilic-grain-disease)
• [Globular Glial Tauopathy](/diseases/globular-glial-tauopathy)
• [FTDP-17](/diseases/ftdp-17)
• [Tauopathy Comparison Matrix](/diseases/tauopathy-comparison)
• [4R-Tauopathies Genetics](/diseases/4r-tauopathies-genetics)

References