Preclinical and clinical issues in Alzheimer's disease drug research and development
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-ß- peptide (Aß), produced by b...
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Frontiers Media SA
2021
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| author | Silvana Gaetani Cesare Mancuso |
| author_browse | Cesare Mancuso Silvana Gaetani |
| author_facet | Silvana Gaetani Cesare Mancuso |
| author_sort | Silvana Gaetani |
| collection | Directory of Open Access Books |
| description | Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-ß- peptide (Aß), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. Aß was also shown to contribute to AD pathology by stimulating the hyperphosphorylation of tau which is responsible for the formation of neurofibrillary tangles. However, the “amyloid cascade hypothesis” was challenged by other theories which lend support to the idea that Aß is not causative but can be considered as an “innocent bystander” in AD. Although preclinical research generated impressive lines of evidence about the several intracellular mechanism(s) whose impairment leads to the onset and progression of AD, clinical research aimed at the development of new drugs capable of preventing or delaying the onset of neuronal damage in AD patients has produced limited results. The drugs currently available for the treatment of AD are acetylcholinesterase inhibitors (AChEI) and the NMDA glutamate receptor antagonist memantine. The AChEI increase acetylcholine levels in the synaptic cleft, which are reduced because of the progressive damage of cholinergic neurons in cognitive brain areas (e.g. amygdala, hippocampus, and frontal cortex), whereas memantine is used to prevent/reduce calcium-dependent excitotoxic neuronal cell death. Both classes of drugs have been shown to improve symptoms related to cognitive decline, but their effects are confined largely to patients with mild to moderate AD, in particular during the first year or so of treatment. An alternative to this symptomatic treatments involves the use of drugs that intervene in the pathogenesis of the disease. Recently, monoclonal antibodies against Aß were proposed as novel agents capable to remove Aß from the brain thus preventing neuronal damage. The research topic focuses on the preclinical and clinical evidence about the several factors that contribute to the pathogenesis of AD as well as the potential therapeutic role of new classes of drugs still under preclinical or clinical development. |
| format | Online |
| id | doab-20.500.12854ir-56874 |
| institution | Directory of Open Access Books |
| language | eng |
| publishDate | 2021 |
| publishDateRange | 2021 |
| publishDateSort | 2021 |
| publisher | Frontiers Media SA |
| publisherStr | Frontiers Media SA |
| record_format | ojs |
| spelling | doab-20.500.12854ir-568742024-04-01T14:14:55Z Preclinical and clinical issues in Alzheimer's disease drug research and development Silvana Gaetani Cesare Mancuso RM1-950 Q1-390 preclinical studies neurodegeneration Clinical Trials as Topic drug research and development Alzheimer's disease thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKG Pharmacology Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive dysfunction and memory loss, inability to perform the activities of daily living and mood disorders. According to the so-called “amyloid cascade hypothesis”, amyloid-ß- peptide (Aß), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. Aß was also shown to contribute to AD pathology by stimulating the hyperphosphorylation of tau which is responsible for the formation of neurofibrillary tangles. However, the “amyloid cascade hypothesis” was challenged by other theories which lend support to the idea that Aß is not causative but can be considered as an “innocent bystander” in AD. Although preclinical research generated impressive lines of evidence about the several intracellular mechanism(s) whose impairment leads to the onset and progression of AD, clinical research aimed at the development of new drugs capable of preventing or delaying the onset of neuronal damage in AD patients has produced limited results. The drugs currently available for the treatment of AD are acetylcholinesterase inhibitors (AChEI) and the NMDA glutamate receptor antagonist memantine. The AChEI increase acetylcholine levels in the synaptic cleft, which are reduced because of the progressive damage of cholinergic neurons in cognitive brain areas (e.g. amygdala, hippocampus, and frontal cortex), whereas memantine is used to prevent/reduce calcium-dependent excitotoxic neuronal cell death. Both classes of drugs have been shown to improve symptoms related to cognitive decline, but their effects are confined largely to patients with mild to moderate AD, in particular during the first year or so of treatment. An alternative to this symptomatic treatments involves the use of drugs that intervene in the pathogenesis of the disease. Recently, monoclonal antibodies against Aß were proposed as novel agents capable to remove Aß from the brain thus preventing neuronal damage. The research topic focuses on the preclinical and clinical evidence about the several factors that contribute to the pathogenesis of AD as well as the potential therapeutic role of new classes of drugs still under preclinical or clinical development. 2021-02-11T23:45:11Z 2021-02-11T23:45:11Z 2016-01-19 14:05:46 2015 book 18188 16648714 9782889194339 https://directory.doabooks.org/handle/20.500.12854/56874 eng Frontiers Research Topics image/jpeg Attribution 4.0 International http://www.frontiersin.org/books/Preclinical_and_clinical_issues_in_Alzheimer%E2%80%99s_disease_drug_research_and_development/453 http://journal.frontiersin.org/researchtopic/1668/preclinical-and-clinical-issues-in-alzheimers-disease-drug-research-and-development Frontiers Media SA 10.3389/978-2-88919-433-9 10.3389/978-2-88919-433-9 bf5ce210-e72e-4860-ba9b-c305640ff3ae 9782889194339 100 open access |
| spellingShingle | RM1-950 Q1-390 preclinical studies neurodegeneration Clinical Trials as Topic drug research and development Alzheimer's disease thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKG Pharmacology Silvana Gaetani Cesare Mancuso Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title | Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title_full | Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title_fullStr | Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title_full_unstemmed | Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title_short | Preclinical and clinical issues in Alzheimer's disease drug research and development |
| title_sort | preclinical and clinical issues in alzheimer s disease drug research and development |
| topic | RM1-950 Q1-390 preclinical studies neurodegeneration Clinical Trials as Topic drug research and development Alzheimer's disease thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKG Pharmacology |
| topic_facet | RM1-950 Q1-390 preclinical studies neurodegeneration Clinical Trials as Topic drug research and development Alzheimer's disease thema EDItEUR::M Medicine and Nursing::MK Medical specialties, branches of medicine::MKG Pharmacology |
| url | 18188 |
| work_keys_str_mv | AT silvanagaetani preclinicalandclinicalissuesinalzheimersdiseasedrugresearchanddevelopment AT cesaremancuso preclinicalandclinicalissuesinalzheimersdiseasedrugresearchanddevelopment |