Preclinical and clinical issues in Alzheimer’s disease drug research and development. Mancuso, C. and Gaetani, S. Frontiers Media SA, March, 2015.
abstract   bibtex   
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.
@book{mancuso_preclinical_2015,
	title = {Preclinical and clinical issues in {Alzheimer}’s disease drug research and development},
	isbn = {978-2-88919-433-9},
	abstract = {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.},
	language = {en},
	publisher = {Frontiers Media SA},
	author = {Mancuso, Cesare and Gaetani, Silvana},
	month = mar,
	year = {2015}
}
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