The blood-brain barrier (BBB) presents a significant challenge for treating corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), limiting CNS penetration of most therapeutic agents. Understanding BBB dysfunction in these tauopathies and employing strategies to enhance drug delivery is critical for developing effective treatments.
CBS and PSP are 4R-tauopathies characterized by tau protein accumulation in neurons and glia. BBB dysfunction contributes to disease pathogenesis through impaired clearance of toxic proteins, neuroinflammation, and compromised delivery of therapeutic agents. This page covers BBB dysfunction mechanisms in CBS/PSP and strategies to overcome delivery barriers[@sweeney2019].
The BBB is a specialized neurovascular interface comprising:
The blood-brain barrier (BBB) presents a significant challenge for treating corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), limiting CNS penetration of most therapeutic agents. Understanding BBB dysfunction in these tauopathies and employing strategies to enhance drug delivery is critical for developing effective treatments.
CBS and PSP are 4R-tauopathies characterized by tau protein accumulation in neurons and glia. BBB dysfunction contributes to disease pathogenesis through impaired clearance of toxic proteins, neuroinflammation, and compromised delivery of therapeutic agents. This page covers BBB dysfunction mechanisms in CBS/PSP and strategies to overcome delivery barriers[@sweeney2019].
The BBB is a specialized neurovascular interface comprising:
| Modality | Findings in CBS/PSP |
|----------|---------------------|
| DCE-MRI | Increased BBB permeability in basal ganglia, brainstem |
| DSC-MRI | Elevated Ktrans in affected regions |
| PET (TSPO) | Microglial activation coinciding with BBB disruption |
| FDG-PET | Hypometabolism in regions with compromised BBB |
| Biomarker | Change | Interpretation |
|-----------|--------|----------------|
| Albumin ratio (CSF/serum) | Elevated | Reduced BBB integrity |
| MMP-9 | Elevated | Tight junction degradation |
| sPDGFR-β | Elevated | Pericyte injury marker |
| Claudin-5 | Decreased in CSF | Tight junction loss |
Mannitol
| Agent | Mechanism | Status |
|-------|-----------|--------|
| Sodium caprylate | Tight junction modulation | Preclinical |
| Cereport (Bradycor) | Transient opening via PKC | Discontinued |
| Tween-80 | P-gp inhibition + membrane fluidization | Veterinary use only |
Focused ultrasound (FUS) with microbubbles temporarily disrupts the BBB through:
| System | Features | Use |
|--------|----------|-----|
| Insightec ExAblate | MR-guided, transcranial | Clinical trials |
| SonoCloud | Implantable, repeated treatments | Research |
| Navier RX | High-intensity, transcranial | Preclinical |
Receptor-mediated transcytosis (RMT) exploits endogenous transport systems to shuttle therapeutics across the BBB.
| Receptor | Endogenous Ligand | Therapeutic Cargo | Status |
|----------|------------------|-------------------|--------|
| Transferrin receptor | Transferrin | Antibodies, nanoparticles | Clinical trials |
| Insulin receptor | Insulin | Peptides, oligonucleotides | Preclinical |
| LDL receptor | Apolipoprotein E | Lipid nanoparticles | Research |
| LRP1 | Amyloid-beta | Peptide conjugates | Research |
Anti-Transferrin Receptor Antibodies
Intranasal delivery bypasses the BBB via:
| Agent | Target | Stage |
|-------|--------|-------|
| Intranasal insulin | Cognition | Clinical trials |
| Intranasal LDOPA | Dopamine replacement | Research |
| Intranasal NAC | Oxidative stress | Phase 2 |
| Exenatide | GLP-1 | Phase 2 |
| Serotype | CNS Tropism | BBB Penetration | Clinical Use |
|----------|-------------|-----------------|--------------|
| AAV9 | Neurons, astrocytes | Moderate | Zolgensma (SMA) |
| AAV-PHP.B | High CNS | Enhanced | Research |
| AAV2 | Limited | Low | Clinical trials |
The success of COVID-19 mRNA vaccines demonstrates LNP capability for CNS delivery.
| Strategy | Examples | Consideration |
|----------|----------|----------------|
| High-affinity transporters | Glucose analogs | Competition with endogenous |
| P-gp substrates | Modified to avoid | Efflux pump avoidance |
| Lipophilicity optimization | SAR modifications | Balance with solubility |
| Trial | Intervention | Indication | Phase |
|-------|--------------|------------|-------|
| NCT04118743 | FUS + Pembrolizumab | Glioblastoma | Phase 1 |
| NCT03739905 | FUS + Trastuzumab | Brain metastases | Phase 1 |
| NCT04480355 | FUS + Rituximab | CNS lymphoma | Phase 1 |
| Trial | Method | Therapeutic | Status |
|-------|--------|-------------|--------|
| FUS + GDNF | Focused ultrasound | Parkinson's | Phase 1 |
| AAV-GAD | Gene therapy | Parkinson's | Phase 2 |
| Intranasal insulin | Nasal spray | Alzheimer's | Phase 2/3 |
Recent studies have advanced FUS-mediated BBB opening for tau antibody delivery. Yang et al. (2024) demonstrated that FUS treatment in 4R-tauopathy mouse models significantly enhanced tau antibody penetration into brain tissue, with a 3-4 fold increase in antibody concentrations compared to systemic delivery alone[@yang2024]. Mueller et al. (2025) showed that combining FUS with anti-tau antibody BIIB080 resulted in reduced tau pathology in hippocampus and basal ganglia regions, with synergistic effects on tau clearance mechanisms[@mueller2025].
Chen et al. (2024) investigated RMT across the BBB in tauopathies, demonstrating that modified transferrin receptor antibodies can deliver therapeutic cargo to neurons and glia affected by tau pathology[@chen2024]. This approach shows promise for targeted delivery of anti-tau oligonucleotides and antibodies.
Kim et al. (2025) developed lipid nanoparticles capable of delivering anti-tau siRNA across the BBB, achieving significant knockdown of tau expression in mouse models of PSP[@kim2025]. The LNP surface was optimized with ApoE-derived peptides to enhance LRP1-mediated transcytosis.
Patel et al. (2025) explored ApoE-derived peptide enhancement of immunotherapy delivery in PSP patients, demonstrating improved CNS penetration of systemically administered anti-tau antibodies[@patel2025]. Iyer et al. (2025) used dynamic contrast-enhanced MRI to quantify BBB permeability changes in PSP patients, showing elevated Ktrans values in the basal ganglia and brainstem compared to healthy controls[@iyer2025].
| Strategy | Rationale |
|----------|-----------|
| FUS + immunotherapy | Enhanced antibody brain penetration |
| Nasal + systemic | Complementary delivery pathways |
| RMT + nanoparticles | Receptor-targeted CNS delivery |