Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets
Abstract
:1. Introduction
2. Risk Factors and Biomarkers of Alzheimer’s Disease
2.1. Risk Factors
2.1.1. Environmental
2.1.2. Genetic
2.2. Biomarkers
2.2.1. CSF and Neuroimaging
2.2.2. Blood-Based
2.3. Time Course of Biomarkers
2.3.1. Clinical View
2.3.2. Research View
3. Hypotheses of Alzheimer’s Disease
3.1. Amyloid Hypothesis
3.2. Amyloid Beta Pathology
3.3. Tau Hypothesis
3.4. Tau Protein Pathology
3.5. Mitochondrial Hypothesis
3.6. Mitochondrial Dysfunction
3.7. Synaptoplasticity Hypothesis
3.8. Neuroinflammation
3.9. Metabolic Dysregulation
3.10. Protein Degradation Deficiency
4. Linking the Amyloid, Tau, and the Mitochondrial Hypotheses of Alzheimer’s Disease
4.1. Integrative Models
4.2. Mitochondrial Targets of Amyloid Beta
4.3. Mitochondrial Targets of Tau
5. Alzheimer’s Drugs
5.1. Cellular Drug Targets
5.2. Approved Drugs
Drug | Primary Action Included | Reference |
---|---|---|
Rivastigmine | Cholinesterase inhibition | [351] |
Galantamine | [352] | |
Donepezil | [352] | |
Memantine | Blockade of NMDA receptor | [353] |
Aducanumab * | Monoclonal antibody directed at brain Aβ plaques and oligomers | [349] |
5.3. Drug Candidates
Drug | Primary Brain Action Included | Clinical Trials | Reference |
---|---|---|---|
Disease-modifying molecules | |||
Metformin | Improving of glucose metabolism; mitochondrial complex I inhibition | Phase 3 | [354,355] |
Semaglutide | Glucagon-like peptide-1 agonism; improving of glycemic control; anti-inflammation | Phase 3 | [356] |
Tricaprylin | Ketosis and improving of mitochondrial function | Phase 3 | [357,358] |
Omega-3 PUFA | Anti-inflammation; antioxidant; synaptic plasticity; cerebrovascular function; blood flow | Phase 3 | [359] |
Icosapent ethyl | Phase 3 | [360] | |
Blarcamesine | σ1 receptor agonism; reduction of Aβ and NFTs; anti-inflammation; amelioration of mitochondrial dysfunction and oxidative stress; antiapoptotic; induction of neurogenesis | Phase 3 | [361,362] |
Atuzaginstat | Inhibition of gingipains; reduction of neurodegeneration and neuroinflammation | Phase 3 | [363] |
AGB101 | Inhibition of SV2A; reduction of Aβ pathology | Phase 3 | [364,365] |
Simufilam | Reduction of P-tau and Aβ aggregates; reduction of α7 nicotinic acetylcholine, NMDA, and insulin receptor dysfunction | Phase 3 | [366] |
Homotaurine (ALZ-801) | Inhibition of Aβ aggregation; GABAA receptor agonism | Phase 3 | [367,368] |
NE3107 | Anti-inflammation | Phase 3 | [369] |
Curcumin | Anti-inflammation; antioxidant; dual inhibition of Aβ and tau aggregation | Phase 2 | [337,371,372,373] |
Gantenerumab | Monoclonal antibody directed at brain Aβ | Phase 3 | [374,375] |
Lecanemab | Phase 3 | [375] | |
Donanemab | Phase 3 | [376] | |
Solanezumab | Phase 3 | [374,377] | |
Neuropsychiatric drugs | |||
Escitalopram | Selective serotonin reuptake inhibition | Phase 3 | [385] |
Brexpiprazole | D2 receptor antagonism | Phase 3 | [386] |
Dextromethorphan/bupropion | NMDA receptor agonism | Phase 3 | [387] |
Deudextromethorphan/quinidine | Agonism σ1 and antagonism NMDA receptor; serotonin–norepinephrine reuptake inhibition | Phase 3 | [388] |
Nabilone | Cannabinoid receptors agonism | Phase 3 | [389] |
Dronabinol | Phase 2 | [389] | |
Cannabidiol | Phase 2 | [389,390] | |
Cognitive enhancers | |||
Caffeine | Antagonism of adenosine A2A receptor; mitochondrial function | Phase 3 | [378,379] |
Guanfacine | α2A-adrenergic receptor agonism | Phase 3 | [380] |
Octohydroaminoacridine succinate | Acetylcholinesterase inhibition | Phase 3 | [381] |
Nicotine | Nicotinic acetylcholine receptor agonism | Phase 2 | [382,383] |
AD-35 | Acetylcholinesterase inhibition; disassembly of Aβ aggregates | Phase 2 | [384] |
5.4. Supplements
6. Conclusions
Funding
Institutional Review Board Statement
Conflicts of Interest
References
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Fišar, Z. Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets. Biomolecules 2022, 12, 1676. https://doi.org/10.3390/biom12111676
Fišar Z. Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets. Biomolecules. 2022; 12(11):1676. https://doi.org/10.3390/biom12111676
Chicago/Turabian StyleFišar, Zdeněk. 2022. "Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets" Biomolecules 12, no. 11: 1676. https://doi.org/10.3390/biom12111676