Preclinical and clinical issues in Alzheimer’s disease drug research and development

Preclinical and clinical issues in Alzheimer’s disease drug research and development

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Alzheimera€™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 a€œamyloid cascade hypothesisa€, amyloid-AŸ- peptide (AAŸ), produced by beta- and gamma- secretase-mediated cleavages of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of AD. AAŸ 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 a€œamyloid cascade hypothesisa€ was challenged by other theories which lend support to the idea that AAŸ is not causative but can be considered as an a€œinnocent bystandera€ 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 AAŸ were proposed as novel agents capable to remove AAŸ 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.BRAIN TISSUE DISSECTION Adult male and female Tg2576 (Brecht et al., 2005) mice were sacrificed by cervical ... The primary antibody used for western blot analysis are: rabbit amyloid precursor protein (AI²PP) 1:2000 (SigmaAldrich, USA ), rabbit SUMO-1 1:1000 (Cell Signaling, USA), ... and hippocampus using the Trizol reagent (Invitrogen, Carlsbad, CA) according to the manufacturera#39;s instruction.

Title:Preclinical and clinical issues in Alzheimer’s disease drug research and development
Author:Cesare Mancuso, Silvana Gaetani
Publisher:Frontiers Media SA - 2015-03-03


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