The Notch signaling pathway is a highly conserved cell-cell communication system that plays critical roles in neural development, synaptic plasticity, and neuronal survival. Dysregulation of Notch signaling has been implicated in multiple neurodegenerative diseases, making it an attractive therapeutic target. This page reviews Notch pathway modulators in development for Alzheimer's disease, Parkinson's disease, ALS, and CBS/PSP.
**Notch Pathway Therapeutic Approaches**
Approach
Mechanism
Disease Focus
Status
Gamma-Secretase InhibitorsBlock Notch cleavage
AD, cancer
Discontinued for AD
Gamma-Secretase Modulators Shift Aβ profile
AD
Clinical trials
Notch Inhibitors Receptor-level blockade
ALS, cancer
Preclinical/clinical
Notch Activators Enhance signaling
Synaptic plasticity
Research
flowchart TD
A["Notch Ligand<br>Delta/Jagged"] --> B["Notch Receptor"]
B --> C["Proteolytic Cleavage<br>ADAM/TACE"]
C --> D["Gamma-Secretase<br>Cleavage"]
D --> E["Notch Intracellular<br>Domain NICD"]
E --> F["Nuclear Translocation"]
F --> G["Transcriptional<br>Activation"]
G --> H["Target Genes:<br>Hes, Hey, Myc"]
Notch Receptors : Notch1-4 (Notch1/2 in CNS)Notch Ligands : Delta-like (DLL1, DLL3, DLL4), Jagged (JAG1, JAG2)Proteases : ADAM17/TACE (S2 cleavage), Gamma-secretase (S3 cleavage)Transcriptional Effectors : RBP-Jκ, NICD, co-activators (Mastermind)
Notch-APP crosstalk is complex in AD:
Gamma-Secretase : Same enzyme processes APP and NotchCompetition : APP and Notch compete for gamma-secretaseAβ Effects : Aβ can alter Notch signalingNeuronal Loss : Notch dysregulation contributes to neuronal death
Notch signaling supports dopaminergic neurons :
Survival : Notch1 promotes dopaminergic neuron survivalNeurogenesis : Notch affects subventricular zone neurogenesisInflammation : Notch regulates microglial activationTherapeutic Potential : Notch modulation may protect neurons
EPHA4 is a Notch pathway modifier in ALS:
Axonal Regeneration : EPHA4 inhibition improves regenerationNotch Connection : EPHA4 intersects with Notch signalingTherapeutic Target : EPHA4/Notch modulation as approach
Tau -Notch interactions are emerging:
Pathological Interaction : Tau affects Notch processingNeuronal Dysfunction : Altered Notch disrupts neuronal functionTherapeutic Implications : Targeting tau-Notch axis
Unlike inhibitors, GSMs shift APP processing without completely blocking gamma-secretase:
Allosteric Modulation : Bind to gamma-secretase allostericallyAβ42 ReductionShorter Aβ : Increase Aβ38/40 productionPreserved Notch : Spare Notch signaling
¶ Clinical Candidates
Compound
Company
Stage
Notes
Semaglintide
Merck
Phase 3 (discontinued)
Oral GSM
CHF-5074
Chiesi
Phase 2
Long-term treatment
E2012
Eisai
Phase 1/2
Brain-penetrant
GSM-1
Multiple
Preclinical
Various
Notch Side Effects : Potential for Notch-related toxicityNarrow Therapeutic Window : Limited margin between efficacy and toxicityEfficacy : Mixed results in clinical trials
Newer approaches aim for selectivity:
Targeted GSMs : More selective for APP over NotchASAPs : Gamma-secretase activating proteins as targetsFragment-Based : Smaller molecules with better selectivity
Antibodies : Anti-Notch receptor antibodiesSmall Molecules : Gamma-secretase inhibitors (GSI)Decoys : Soluble Notch ligands as decoys
¶ Clinical Candidates
Drug
Target
Company
Status
RO4929097
GSI
Roche
Discontinued (cancer)
MK-0752
GSI
Merck
Discontinued (cancer)
BMS-986202
Notch1 antibody
Bristol-Myers
Preclinical
ALS : Notch inhibition may reduce excitotoxicityBrain Tumors : Glioma applications inform CNS penetration
Paradoxically, activating Notch may benefit some conditions:
Synaptic Plasticity : Notch enhances memory formationNeuronal Survival : Notch1 activation protects neuronsNeurogenesis : Stimulates neural progenitor activity
Agonistic Antibodies : Activate Notch receptorsSmall Molecule Activators : Enhance ligand-receptor interactionGene Therapy : Increase Notch expression
Approach
Target
Company
Development Stage
GSM (CHF-5074)
Gamma-secretase
Chiesi
Phase 2
GSM (E2012)
Gamma-secretase
Eisai
Phase 1/2
Notch1 activator
Notch1
Research
Preclinical
GSI
Gamma-secretase
Multiple
Discontinued
Approach
Target
Company
Development Stage
Notch1 agonist
Notch1
Research
Preclinical
Notch3 modulation
Notch3
Research
Preclinical
Approach
Target
Company
Development Stage
EPHA4 inhibitor
EPHA4
Research
Preclinical
Notch modulation
Notch
Research
Preclinical
Approach
Target
Development Stage
Tau-Notch targeting
Tau/Notch
Research
Aβ42/40 Ratio : GSM efficacy markerNotch Target Genes : Hes1 expressionNeuroimaging : PET for amyloid/tauCSF Markers : Aβ, tau, NFL
Genetic Status : APP/ApoE genotypeDisease Stage : Early vs. advancedBiomarker Profile : Baseline pathology
Notch-Related Toxicities : Gastrointestinal, hematologicalSkin Effects : Altered keratinocyte differentiationImmune Function : Infectious complications