Therapeutic Targets Index

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Therapeutic Targets in Neurodegeneration

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Therapeutic Targets in Neurodegeneration

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">Therapeutic Targets Index</th>
</tr>
<tr>
<td class="label">Target</td>
<td>Description</td>
</tr>
<tr>
<td class="label">[Amyloid-beta (Aβ42/Aβ40)](/proteins/amyloid-beta)</td>
<td>Core pathogenic peptide forming plaques</td>
</tr>
<tr>
<td class="label">[Amyloid Precursor Protein (APP)](/proteins/app)</td>
<td>Source of all amyloid-beta peptides</td>
</tr>
<tr>
<td class="label">[BACE1 (Beta-secretase)](/proteins/bace1)</td>
<td>Protease that initiates Aβ production</td>
</tr>
<tr>
<td class="label">[Gamma-secretase](/entities/psen1-protein)</td>
<td>Final protease in Aβ production</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Description</td>
</tr>
<tr>
<td class="label">[Tau protein (MAPT)](/proteins/tau)</td>
<td>Microtubule-associated protein that forms NFTs</td>
</tr>
<tr>
<td class="label">Tau phosphorylation</td>
<td>Abnormal phosphorylation by kinases</td>
</tr>
<tr>
<td class="label">Tau aggregation</td>
<td>Oligomerization and fibril formation</td>
</tr>
<tr>
<td class="label">Tau propagation</td>
<td>Prion-like spread between [neurons](/entities/neurons)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Description</td>
</tr>
<tr>
<td class="label">[α-Synuclein (SNCA)](/proteins/alpha-synuclein)</td>
<td>Prion-like protein forming Lewy bodies</td>
</tr>
<tr>
<td class="label">α-Synuclein aggregation</td>
<td>Oligomer and fibril formation</td>
</tr>
<tr>
<td class="label">α-Synuclein clearance</td>
<td>Autophagy and lysosomal degradation</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Description</td>
</tr>
<tr>
<td class="label">[TREM2](/proteins/trem2-protein)</td>
<td>Microglial receptor regulating phagocytosis</td>
</tr>
<tr>
<td class="label">[NLRP3 Inflammasome](https://neurowiki.local/investment/nlrp3-inflammasome)</td>
<td>Inflammatory cytokine activation</td>
</tr>
<tr>
<td class="label">CD33</td>
<td>Microglial receptor affecting Aβ clearance</td>
</tr>
<tr>
<td class="label">[CSF1R](https://neurowiki.local/cell-types/microglia)</td>
<td>Microglial survival factor</td>
</tr>
<tr>
<td class="label">[TYROBP (DAP12)](/genes/tyrobp)</td>
<td>[TREM2](/proteins/trem2) signaling adaptor</td>
</tr>
<tr>
<td class="label">Gene</td>
<td>Protein</td>
</tr>
<tr>
<td class="label">[LRRK2](/genes/lrrk2)</td>
<td>Leucine-rich repeat kinase 2</td>
</tr>
<tr>
<td class="label">[GBA](/entities/gba)</td>
<td>Glucocerebrosidase</td>
</tr>
<tr>
<td class="label">[SNCA](/proteins/alpha-synuclein)</td>
<td>Alpha-synuclein</td>
</tr>
<tr>
<td class="label">[PARKIN](/genes/parkin)</td>
<td>Parkin</td>
</tr>
<tr>
<td class="label">[PINK1](/genes/pink1)</td>
<td>PTEN-induced kinase 1</td>
</tr>
<tr>
<td class="label">[DJ1](/genes/dj1)</td>
<td>DJ-1</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Description</td>
</tr>
<tr>
<td class="label">Complex I</td>
<td>Electron transport chain deficits</td>
</tr>
<tr>
<td class="label">TFAM</td>
<td>Mitochondrial transcription factor</td>
</tr>
<tr>
<td class="label">PGC-1α</td>
<td>Mitochondrial biogenesis regulator</td>
</tr>
<tr>
<td class="label">Mitophagy regulators</td>
<td>PINK1, PARKIN pathway</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Pathway</td>
</tr>
<tr>
<td class="label">Autophagy-lysosome pathway</td>
<td>Protein clearance</td>
</tr>
<tr>
<td class="label">[Ubiquitin-proteasome system](/mechanisms/ubiquitin-proteasome-system)</td>
<td>Protein degradation</td>
</tr>
<tr>
<td class="label">Molecular chaperones</td>
<td>Protein folding</td>
</tr>
<tr>
<td class="label">[mTOR](/mechanisms/mtor-signaling-pathway)</td>
<td>Autophagy inhibition</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Drug Examples</td>
</tr>
<tr>
<td class="label">[Acetylcholinesterase](/proteins/ache)</td>
<td>[Donepezil](/entities/donepezil), [Rivastigmine](/entities/rivastigmine), Galantamine</td>
</tr>
<tr>
<td class="label">Muscarinic receptors (M1)</td>
<td>Xanomeline</td>
</tr>
<tr>
<td class="label">Nicotinic receptors (α7)</td>
<td>Agonists in development</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Drug Examples</td>
</tr>
<tr>
<td class="label">[Dopamine replacement](https://neurowiki.local/therapeutics/levodopa)</td>
<td>Levodopa/Carbidopa</td>
</tr>
<tr>
<td class="label">[Dopamine agonists](https://neurowiki.local/therapeutics/dopamine-agonists)</td>
<td>Pramipexole, Rotigotine</td>
</tr>
<tr>
<td class="label">[MAO-B inhibitors](https://neurowiki.local/therapeutics/mao-b-inhibitors)</td>
<td>Rasagiline, Selegiline</td>
</tr>
<tr>
<td class="label">[COMT inhibitors](https://neurowiki.local/therapeutics/comt-inhibitors)</td>
<td>Entacapone, Opicapone</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Drug Examples</td>
</tr>
<tr>
<td class="label">[NMDA receptor](/proteins/grin1)</td>
<td>Memantine</td>
</tr>
<tr>
<td class="label">Target Class</td>
<td>Compounds in Development</td>
</tr>
<tr>
<td class="label">Anti-amyloid immunotherapy</td>
<td>8+</td>
</tr>
<tr>
<td class="label">Anti-tau immunotherapy</td>
<td>6+</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>4+</td>
</tr>
<tr>
<td class="label">Synaptic plasticity</td>
<td>3+</td>
</tr>
<tr>
<td class="label">Target Class</td>
<td>Compounds in Development</td>
</tr>
<tr>
<td class="label">Alpha-synuclein</td>
<td>10+</td>
</tr>
<tr>
<td class="label">LRRK2</td>
<td>4+</td>
</tr>
<tr>
<td class="label">GBA/GCase</td>
<td>3+</td>
</tr>
<tr>
<td class="label">Neuroinflammation</td>
<td>5+</td>
</tr>
</table>

Overview

This index provides a comprehensive overview of molecular and cellular targets being pursued for developing disease-modifying therapies for neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), ALS, and related disorders. Each target is linked to detailed mechanism pages, treatment approaches, and the current drug development pipeline.

Neurodegenerative diseases share common pathological mechanisms including protein aggregation, mitochondrial dysfunction, neuroinflammation, and impaired [autophagy](/entities/autophagy). This page catalogs therapeutic targets across these mechanisms and their relationship to specific diseases. [@molecular2024]

Amyloid-Based Targets (Alzheimer's Disease)

The amyloid cascade hypothesis posits that accumulation of amyloid-beta (Aβ) plaques is the primary trigger in Alzheimer's disease pathogenesis. Multiple therapeutic approaches target amyloid production, aggregation, and clearance. [@amyloid2024]

Key Targets

Mechanism Pages

[Amyloid Cascade Pathway](/mechanisms/amyloid-cascade-pathway)
[Amyloid-Beta Aggregation and Plaque Formation](/mechanisms/amyloid-aggregation)
[Amyloid Clearance Mechanisms](/mechanisms/amyloid-clearance)
[APP Amyloid Pathway in Alzheimer's Disease](/mechanisms/app-amyloid-pathway-alzheimers)

Treatment Pages

[Anti-Amyloid Therapeutics](/therapeutics/anti-amyloid-therapeutics)
[Lecanemab (Leqembi)](/therapeutics/lecanemab)
[Donanemab (Kisunla)](/therapeutics/donanemab)
[Aducanumab (Aduhelm)](/therapeutics/aducanumab)
[Gantenerumab](/therapeutics/gantenerumab)
[BACE Inhibitors](/therapeutics/bace-inhibitors)
[Gamma-Secretase Modulators](/therapeutics/gamma-secretase-modulators)

Tau-Based Targets

[Tau](/proteins/tau) pathology correlates strongly with cognitive decline in AD and is the primary hallmark in tauopathies like progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Tau-targeting therapies aim to reduce phosphorylation, aggregation, and propagation. [@tautargeted2024]

Key Targets

Mechanism Pages

[Tau Pathology Pathway](/mechanisms/tau-pathology-pathway)
[Tau Hyperphosphorylation and Neurofibrillary Tangles](/mechanisms/tau-hyperphosphorylation)
[Tau Seeding and Propagation Pathway](/mechanisms/tau-seeding-propagation)
[4R Tauopathy Molecular Mechanisms](/mechanisms/4r-tauopathy-mechanisms)
[Tau-Heparan Sulfate Interaction](/mechanisms/tau-heparan-sulfate-interaction)

Treatment Pages

[Tau-Targeted Therapeutics](/therapeutics/tau-targeted-therapeutics)
[Anti-Tau Therapeutics](/therapeutics/anti-tau-therapeutics)
[Tau-Targeting Therapeutics Pipeline](/therapeutics/tau-therapeutics-pipeline)

Alpha-Synuclein Targets (Parkinson's Disease)

Alpha-synuclein (α-Syn) aggregation is the central pathogenic mechanism in Parkinson's disease and related synucleinopathies. Multiple therapeutic strategies aim to reduce α-Syn production, aggregation, or enhance clearance. [@alphasynuclein2024]

Key Targets

Mechanism Pages

[Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway)
[Alpha-Synuclein Propagation Mechanisms](/mechanisms/alpha-synuclein-propagation-mechanisms)
[Alpha-Synuclein Clearance Mechanisms](/mechanisms/alpha-synuclein-clearance)
[Synucleinopathies](/mechanisms/synucleinopathies)

Treatment Pages

[Alpha-Synuclein Immunotherapy](/therapeutics/alpha-synuclein-immunotherapy)
[Alpha-Synuclein Aggregation Inhibitors](/therapeutics/alpha-synuclein-aggregation-inhibitors)
[Alpha-Synuclein-Targeting Therapies](/therapeutics/alpha-synuclein-targeting-therapies)

Neuroinflammation Targets

Chronic neuroinflammation driven by activated [microglia](/cell-types/microglia-neuroinflammation) is a common feature across neurodegenerative diseases. Targeting inflammatory pathways offers potential for disease modification. [@neuroinflammation2024]

Key Targets

Mechanism Pages

[Neuroinflammation Pathway](/mechanisms/neuroinflammation-pathway)
[Microglia and Neuroinflammation in AD](/mechanisms/microglia-neuroinflammation)
[NF-κB Signaling in Neuroinflammation](/mechanisms/nf-kb-signaling-neuroinflammation)

Treatment Pages

[Neuroinflammation Therapeutics](/therapeutics/neuroinflammation-therapeutics)
[TREM2-Targeting Therapeutics](/therapeutics/trem2-therapeutics)
[BTK Inhibitors for Neurodegeneration](/therapeutics/btk-inhibitors-neurodegeneration)

Parkinson's Disease Genetic Targets

Approximately 10-15% of PD cases are linked to monogenic causes. Several genetic targets are being pursued for disease-modifying therapies. [@genetic2024]

Key Targets

Mechanism Pages

[Mitochondrial Quality Control Network Pathway](/mechanisms/mitochondrial-quality-control-network-pathway)
[Mitochondrial Dynamics Pathway](/mechanisms/mitochondrial-dynamics-pathway)
[Mitophagy Pathway](/mechanisms/mitochondrial-quality-control)

Treatment Pages

[LRRK2 Kinase Inhibitors](/therapeutics/lrrk2-inhibitors)
[Ambroxol for Neurodegeneration](/therapeutics/ambroxol-neurodegeneration) (GCase chaperone)
[Gene Therapy for Neurodegenerative Diseases](/therapeutics/gene-therapy)

Mitochondrial Targets

Mitochondrial dysfunction is a hallmark of neurodegeneration, with impaired energy production, increased oxidative stress, and defective quality control. [@mitochondrial2024]

Key Targets

Mechanism Pages

[Mitochondrial Dysfunction Pathway](/mechanisms/mitochondrial-dysfunction-pathway)
[Mitochondrial Dynamics: Fusion and Fission](/mechanisms/mitochondrial-dynamics-fusion-fission)
[ER-Mitochondria Contact Sites](/mechanisms/er-mitochondria-contact-sites)

Treatment Pages

[Mitochondrial Therapeutics](/therapeutics/mitochondrial-therapeutics)
[Coenzyme Q10 for Neurodegeneration](/therapeutics/coq10-neurodegeneration)

Proteostasis Targets

The proteostasis network declines with age, leading to accumulation of misfolded proteins. Enhancing protein clearance pathways is a promising therapeutic strategy. [@proteostasis2024]

Key Targets

Mechanism Pages

[Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosomal-pathway)
[Chaperone-Mediated Autophagy](/mechanisms/chaperone-mediated-autophagy-neurodegeneration)
[Proteostasis Network](/mechanisms/proteostasis-network)

Treatment Pages

[Autophagy-Enhancing Therapies](/therapeutics/autophagy-enhancing-therapies)
[mTOR Inhibitors for Neurodegeneration](/therapeutics/mtor-inhibitors)
[Targeted Protein Degradation (PROTACs)](/therapeutics/targeted-protein-degradation-protacs)

Symptomatic Treatment Targets

While disease-modifying therapies are the ultimate goal, symptomatic treatments remain important for patient quality of life.

Cholinergic System

Dopaminergic System

Glutamatergic System

Drug Development Pipeline Summary

Alzheimer's Disease Phase 3 Pipeline

Parkinson's Disease Phase 2/3 Pipeline

External Links

[ClinicalTrials.gov - Neurodegenerative Disease Trials](https://clinicaltrials.gov/)
[Alzheimer's Association](https://www.alz.org/)
[Parkinson's Foundation](https://www.parkinson.org/)
[NIH - National Institute on Aging](https://www.nia.nih.gov/)

References

[Unknown, Molecular Targets for Neurodegenerative Disease Therapy (2024) (2024)](https://doi.org/10.1016/j.tics.2024.01.001)

[Unknown, Amyloid Cascade Hypothesis: Updated Review (2024) (2024)](https://doi.org/10.1002/alz.13852)

[Unknown, Tau-Targeted Therapeutics in Alzheimer's Disease (2024) (2024)](https://doi.org/10.1038/s41582-024-00845-4)

[Unknown, Alpha-Synuclein Therapies for Parkinson's Disease (2024) (2024)](https://doi.org/10.1002/mds.29847)

[Unknown, Neuroinflammation as Therapeutic Target (2024) (2024)](https://doi.org/10.1038/s41591-024-01985-4)

[Unknown, Genetic Forms of Parkinson's Disease (2024) (2024)](https://doi.org/10.1002/mds.29718)

[Unknown, Mitochondrial Dysfunction in Neurodegeneration (2024) (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.02.001)

[Unknown, Proteostasis Network and Neurodegeneration (2024) (2024)](https://doi.org/10.1016/j.tcb.2024.01.003)

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Therapeutic Targets Index

Therapeutic Targets in Neurodegeneration

Therapeutic Targets in Neurodegeneration

Overview

Amyloid-Based Targets (Alzheimer's Disease)

Key Targets

Mechanism Pages

Treatment Pages

Tau-Based Targets

Key Targets

Mechanism Pages

Treatment Pages

Alpha-Synuclein Targets (Parkinson's Disease)

Key Targets

Mechanism Pages

Treatment Pages

Neuroinflammation Targets

Key Targets

Mechanism Pages

Treatment Pages

Parkinson's Disease Genetic Targets

Key Targets

Mechanism Pages

Treatment Pages

Mitochondrial Targets

Key Targets

Mechanism Pages

Treatment Pages

Proteostasis Targets

Key Targets

Mechanism Pages

Treatment Pages

Symptomatic Treatment Targets

Cholinergic System

Dopaminergic System

Glutamatergic System

Drug Development Pipeline Summary

Alzheimer's Disease Phase 3 Pipeline

Parkinson's Disease Phase 2/3 Pipeline

See Also

External Links

References