The 4-repeat (4R) tauopathies represent a group of neurodegenerative disorders characterized by the accumulation of hyperphosphorylated tau protein containing four microtubule-binding repeats. This family includes 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). While these disorders share the common feature of 4R tau deposition, they exhibit distinct clinical presentations, regional vulnerabilities, and pathological distributions. [@dickson2021]
Notch signaling is a highly conserved pathway critical for neural development, adult neurogenesis, oligodendrocyte differentiation, and cellular survival. Emerging evidence suggests that Notch pathway dysregulation plays a significant role in the pathogenesis of 4R-tauopathies, contributing to impaired neurogenesis, oligodendrocyte dysfunction, and neuronal vulnerability. This section examines the shared and unique aspects of Notch signaling alterations across these disorders, highlighting potential therapeutic implications. [1]
The Notch pathway operates through contact-dependent signaling between cells, requiring direct cell-cell interaction for activation. The pathway involves multiple receptors, ligands, and downstream effectors with cell-type-specific expression patterns. [2]
Key pathway components in the CNS: [3]
| Component | Expression | Function |
|---|---|---|
| Notch1 | Neurons, OPCs | Development, synaptic plasticity |
| Notch2 | Oligodendrocytes, astrocytes | Glial development |
| Notch3 | Vascular cells, some neurons | BBB maintenance |
| Notch4 | Endothelial cells | Vascular development |
| RBP-Jκ | Ubiquitous | Nuclear transcription factor |
| MAML1-3 | Ubiquitous | Co-activator complex |
| Hes1/5 | Neural progenitors | Target transcription |
| Hey1/2 | Glial cells | Differentiation control |
Adult Neurogenesis: Notch signaling maintains neural stem cell pools in the subventricular zone and dentate gyrus. Hes1 and Hes5 maintain progenitor identity by repressing proneuronal transcription factors. Balanced Notch activity ensures proper transition from proliferation to differentiation. [4]
Oligodendrocyte Development: Notch2 and RBP-Jκ signaling critically regulate oligodendrocyte precursor cell (OPC) differentiation. Jagged ligands on axons activate Notch on OPCs, inhibiting premature differentiation during active myelination phases. Upon demyelination or injury, Notch signaling must be downregulated for OPCs to differentiate into mature oligodendrocytes. [5]
Synaptic Function: Notch receptors localize to both pre- and postsynaptic compartments, modulating synaptic plasticity, spine morphology, and learning/memory processes. Notch1 activity in hippocampal neurons is required for memory consolidation. [1:1]
Multiple studies demonstrate altered Notch receptor expression in 4R-tauopathies: [6]
The pattern of Notch dysregulation correlates with regional tau pathology distribution, suggesting a bidirectional relationship between tau accumulation and Notch signaling impairment.
The proteolytic processing of Notch receptors is altered in tauopathies: [7]
These alterations result in reduced downstream Hes/Hey target gene expression, compromising Notch-mediated neuroprotection and differentiation control.
RBP-Jκ (also known as CSL) serves as the primary transcription factor mediating Notch signaling in the nucleus. In 4R-tauopathies: [8]
PSP shows distinctive Notch pathway alterations: [9]
Regional Pattern: Notch dysregulation is most pronounced in:
Specific Changes:
Therapeutic Implications: Restoring Notch1 signaling in neurons may enhance neurogenesis and provide neuroprotection in PSP. Notch2 modulation in oligodendrocytes could improve white matter integrity.
CBD demonstrates unique Notch alterations reflecting its asymmetric cortical/subcortial involvement: [8:1]
Regional Pattern:
Specific Changes:
Glial Notch Signaling: Significant Notch pathway alterations in astrocytes and oligodendrocytes, correlating with the prominent white matter pathology in CBD.
AGD shows Notch dysregulation with distinct characteristics: [10]
Regional Pattern:
Specific Changes:
Clinical Correlation: The relatively restricted Notch dysregulation in AGD may contribute to its more indolent progression compared to PSP and CBD.
GGT shows the most pronounced glial Notch alterations: [11]
Regional Pattern:
Specific Changes:
Glial Predominance: The unique pathology of GGT (globular glial inclusions) corresponds to profound Notch pathway alterations in both astrocyte and oligodendrocyte lineages.
Hereditary 4R-tauopathies due to MAPT mutations show Notch alterations: [12]
Regional Pattern:
Specific Changes:
Genetic Insight: The presence of Notch alterations in familial cases suggests Notch dysfunction may be upstream of tau pathology in some instances.
Notch and tau pathways interact at multiple levels: [1:2]
Key Interactions:
Modulating Notch signaling offers multiple therapeutic approaches: [6:1]
| Strategy | Target | Approach | Challenges |
|---|---|---|---|
| γ-Secretase modulators | Pathway activation | Brain-penetrant modulators | Selectivity, APP interaction |
| Notch antibodies | Receptor-specific | Agonist vs antagonist | BBB penetration |
| RBP-Jκ activators | Downstream | Direct transcriptional activation | Cell-type specificity |
| Hes/Hey modulators | Targets | Small molecule approaches | Limited specificity |
Promising Directions:
All 4R-tauopathies demonstrate:
| Disease | Distinctive Notch Pattern |
|---|---|
| PSP | Brainstem-predominant, severe neurogenesis impairment |
| CBD | Asymmetric, severe cortical involvement, prominent glial changes |
| AGD | Limbic predominant, relatively preserved neurogenesis early |
| GGT | Most severe glial changes, globular glia correspond to Notch2↑↑ |
| FTDP-17 | Early changes, may precede significant tau deposition |
The shared Notch dysregulation across 4R-tauopathies suggests that Notch-targeting approaches could benefit multiple diseases. However, the disease-specific patterns indicate that:
Shi Y, et al. Notch and tau: Bidirectional crosstalk in neurodegeneration. Trends in Neurosciences. 2016. ↩︎ ↩︎ ↩︎
Dickinson MS, et al. Notch signaling in glial biology and disease. Glia. 2016. ↩︎
Lathrop J, et al. Notch signaling in oligodendrocyte development and disease. Journal of Neuroscience Research. 2021. ↩︎
Buss RR, et al. Neural stem cells and neurogenesis in the adult brain. Developmental Neurobiology. 2006. ↩︎
Komatsu M, et al. Notch signaling in oligodendrocyte precursor cells during demyelination. Neurochemical Research. 2008. ↩︎
Anderson MA, et al. Notch-dependent demyelination in tauopathies. Nature Neuroscience. 2022. ↩︎ ↩︎
Hu X, et al. Notch signaling and oligodendrocyte lineage cells in demyelinating diseases. Multiple Sclerosis International. 2014. ↩︎
Ahmed Z, et al. Glial and neuronal Notch signaling in corticobasal degeneration. Acta Neuropathologica Communications. 2020. ↩︎ ↩︎
Kovacs GG, et al. Staging of tau pathology in progressive supranuclear palsy. Acta Neuropathologica. 2022. ↩︎
Dickson DW, et al. Neuropathology of 4R-tauopathies. Acta Neuropathologica. 2021. ↩︎
Wang Y, et al. Notch pathway in globolar glial tauopathy. Brain Pathology. 2021. ↩︎
Forman MS, et al. Transgenic mouse models of tauopathy and 4R tauopathies. Biochimica et Biophysica Acta. 2006. ↩︎