Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound
Abstract
:1. Introduction
2. Ethiopathogenesis of AD
2.1. Amyloid β and Neurofibrillary Tangles
2.2. Relation between Key Player Proteins in AD Pathology and Plasticity
2.2.1. Presenilin 1 (PS1)
2.2.2. Tau
2.2.3. Amyloid-β
2.2.4. APOE
2.3. Neurogenesis in AD
2.3.1. Neurogenesis
2.3.2. Neurogenesis in AD
2.4. Neurodegeneration, Synaptic Deficit, and Synaptic Compensation
2.4.1. Neurodegeneration
2.4.2. Synaptic Deficit
2.4.3. Synaptic Compensation
2.5. Neuroinflammation
2.6. Cognitive Impairment
2.7. Growth Factors and Neurotrophins
3. Development of Drugs for AD
3.1. Shift from Large Molecules to Small Peptidergic Compounds
3.1.1. Peptides as Drugs
3.1.2. Neurotrophic Factor Peptide Mimetics as Potential Drugs for AD
3.1.3. Current Status of AD Approved and Developing Drugs in the Market
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Neuropathological Features | Composition | References |
---|---|---|
Amyloid plaques | Composed of Aβ 40 and Aβ 42 fragments that result from the sequential cleavage of AβPP by the enzymes β-secretase and γ-secretase in neurons. There are two types of amyloid plaques: diffuse and dense core based on their morphology and their positive or negative staining with Thioflavin-S or Congo Red. | [28,29,30,31] |
Dense core plaques | Dense core amyloid plaques stain with thioflavin-S and Congo Red and they are typically surrounded by dystrophic neuritis, reactive astrocytes and activated microglial cells, and are associated with synaptic loss. | [28,29,30,31] |
Diffuse plaques | They are amorphous plaques with an undefined contour and amorphous amyloid deposits which are negatively stained with Congo red and thioflavin S. | [29] |
Amyloid β | Amyloid β: a 40 or 42 amino acid peptide derived from amyloid precursor protein (APP) after its sequential cleavage by β- and γ-secretases. | [29] |
Cerebral amyloid angiopathy (CAA) | It is the consequence of the deposition of Aβ in the vessel walls. The major constituent of CAA is the soluble form of Aβ (Aβ40) | [29] |
Neurofibrillary tangles (NFTs) | They are primarily made up of paired helical filaments (PHFs) that are fibrils of 10 nm in diameter that form pairs with a helical tridimensional conformation at a regular periodicity of ~65 nm They are caused by the aggregation of the hyperphosphorylated tau in neurons of the misfolded tau that become extraneuronal (“ghost” tangles) when tangle-bearing neurons die. | [28,30] |
Neuropil threads | They are axonal and dendritic segments formed by the aggregated and hyperphosphorylated tau that are usually associated with the NFT in AD. | [29] |
Granuovacuolar degeneration (GVD) and Hirano bodies | GVD mainly formed by large double-membrane bodies with an unknown origin and significance. Usually detected in the cytoplasm of hippocampal pyramidal neurons of AD patients. | [31] |
Glial responses (Neuroinflammation) | A significant positive correlation was reported between both astrocytosis and microgliosis and NFT burden but not between both reactive glial cell types and amyloid burden, which suggests that neuroinflammation is tightly linked to neurofibrillary degeneration. | [29,32] |
Neuronal and synaptic loss | Neuronal loss is the major cause of cortical atrophy. Synaptic Loss contributes along with neuronal loss to cortical atrophy. | [11,29,33] |
α-synuclein positive Lewy bodies | AD patients that present α-synuclein positive Lewy bodies exhibit acceleration in the disease process and a more aggressive and rapid cognitive decline compared to pure AD patients. | [34] |
Cognitive decline | Episodic memory is the first area affected in the AD process, followed by impairment in the executive functions, apraxia, visuospatial navigation deficits, visuo-perceptive deficits, and semantic memory, which consequently results the full-blown dementia syndrome. | [29,35] |
Psychiatric Symptoms | Prevalence | References |
---|---|---|
Depression | Its prevalence is around 20–50% in AD patients. | [151,152] |
Apathy | Its prevalence could reach up to 80% Is the most common and persistent neuropsychological feature in AD | [152] |
Agitation, irritability and aggression | Its prevalence is between 48% and 80% with symptoms that persistfor months and happen across all AD stages. | [153,154] |
Anxiety and phobia | Prevalence was reported to range from 7.9% to 29.8% | [152,155] |
Psychotic symptoms (delusions and hallucinations) | The prevalence is between 30–50% in AD. Hallucination was found to diagnose AD with 14% sensitivity and 99% specificity. | [152,156] |
Sleep disorders | Common behavioral disturbances in AD. Prevalence between 25% to 50% of patients ~75% of patients sleep for extended periods during the day. | [152,157] |
Hypokinesia | Could diagnose AD with 30% sensitivity and 99% specificity | [156] |
Paranoia | Could diagnose AD with 15% sensitivity and 99% specificity | [156] |
Rigidity | Could diagnose AD with 16% sensitivity and 100% specificity | [156] |
Tremors | Could diagnose AD with 16% sensitivity and 96% specificity | [156] |
Drug | Effects | References |
---|---|---|
Four cholinesterase inhibitors: Donepezil (Aricept™), rivastigmine (Exelon™), and galantamine (Razadyne™). Tacrine: No longer available on the market | Targets cholinergic innervations in the nucleus basalis. | [207] |
One NMDA receptor antagonist: Memantine (Namenda™). | N-methyl-d-aspartate receptor antagonist (NMDA) that blocks glutamate from binding to its receptors. This prevents excessive excitotoxicity and neuronal cell death, which is thought to contribute to the pathogenesis of AD. | [207,208] |
GV-971 (Oligomannate™), an oligosaccharide | Reduction of systemic inflammation and neuroinflammation - Approved in China | [207] |
Aducanumab | First disease-modifying therapy (DMT). Became available on the market in 2021 for MCI due to AD and mild AD dementia An anti-amyloid monoclonal antibody Accelerated regulatory mechanism based on demonstration of amyloid plaque lowering | [207,209] |
Donanemab and lecanemab | Monoclonal antibodies Under review by the US Food and Drug Administration (FDA). | [210,211] |
Phase 3 clinical trials 31 agents | 21 DMTs (5 biologic and 16 small molecules) | [207] |
Phase 2 clinical trials 82 agents | 71 DMTs (26 biologics and 45 small molecules). | [207] |
Phase 1 clinical trials 30 agents | 27 DMTs (9 biologics and 18 small molecules) | [207] |
Antipsychotic drugs | ||
Acetylcholinesterase inhibitors | May improve apathy, delusions and hallucinations, and less commonly improve aggression, depression, disinhibited behaviors, irritability or nocturnal disruption in patients with mild to moderate dementia | [212] |
Selective serotonin reuptake inhibitors (SSRIs) | Effective in the management of depression and anxiety in people with dementia that cannot be treated by non-pharmacological interventions alone. For AD patients, citalopram was reported to decrease agitation and to likely improve other symptoms such as delusions, suggesting that it may have antipsychotic effect | [213,214] |
Antipsychotics Risperidone, Quetiapine, Olanzapine | Have only a modest effect in managing the psychological symptoms that accompany AD and other neurodegenerative diseases The level of effectiveness of these drugs varies between patients. | [215] |
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Baazaoui, N.; Iqbal, K. Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound. Biomolecules 2022, 12, 1409. https://doi.org/10.3390/biom12101409
Baazaoui N, Iqbal K. Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound. Biomolecules. 2022; 12(10):1409. https://doi.org/10.3390/biom12101409
Chicago/Turabian StyleBaazaoui, Narjes, and Khalid Iqbal. 2022. "Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound" Biomolecules 12, no. 10: 1409. https://doi.org/10.3390/biom12101409
APA StyleBaazaoui, N., & Iqbal, K. (2022). Alzheimer’s Disease: Challenges and a Therapeutic Opportunity to Treat It with a Neurotrophic Compound. Biomolecules, 12(10), 1409. https://doi.org/10.3390/biom12101409