Selective Amyloid-\(\beta\) Lowering Agents
نویسنده
چکیده
The amyloid-β peptide (Aβ), implicated in the pathogenesis of Alzheimer's disease (AD), is produced through sequential proteolysis of the Aβ precursor protein (APP) by βand γ-secretases. Thus, blocking either of these two proteases, directly or indirectly, is potentially worthwhile toward developing AD therapeutics. β-Secretase is a membrane-tethered pepsin-like aspartyl protease suitable for structure-based design, whereas γ-secretase is an unusual, heterotetrameric membrane-embedded aspartyl protease. While γ-secretase inhibitors entered clinical trials first due to their superior pharmacological properties (for example, brain penetration) over β-secretase inhibitors, it has since become clear that γ-secretase inhibitors can cause mechanism-based toxicities owing to interference with the proteolysis of another γ-secretase substrate, the Notch receptor. Strategies for targeting Aβ production at the γ-secretase level without blocking Notch signalling will be discussed. Other strategies utilizing cell-based screening have led to the identification of novel Aβ lowering agents that likewise leave Notch proteolysis intact. The mechanism by which these agents lower Aβ is unknown, but these compounds may ultimately reveal new targets for AD therapeutics. The formation of the amyloid-β peptide (Aβ) from the Aβ precursor protein (APP) is a critical molecular event in the pathogenesis of Alzheimer's disease (AD). For this reason, the proteases that produce Aβ from this integral membrane protein are considered key targets in the prevention and treatment of AD [1]. β-Secretase generates the amino terminus of Aβ, shedding the large ectodomain (β-APPs) and leaving a 99 residue carboxy-terminal fragment (C99) in the membrane. C99 is cleaved in the middle of its transmembrane domain by γ-secretase to produce Aβ. γ-Secretase produces carboxy-terminal variants of Aβ, primarily a 40-residue peptide (Aβ40), but also a small proportion of a 42 residue variant (Aβ42), as well as other minor species. Aβ42 is much more prone to aggregation than Aβ40, and Aβ42 is the major Aβ species found in cerebral plaques that characterize the AD brain. β-Secretase is a membrane-tethered enzyme in the pepsin family of aspartyl proteases and primarily expressed in the brain [2]. Knockout of this enzyme in mice is not lethal and prevents Aβ production in the brain [3,4]. Nevertheless, concern about β-secretase as a target has been raised by the finding that the myelin sheath of peripheral nerves of these knockout mice are much thinner due to the important role β-secretase plays in cleaving neuregulin-1 [5]. The extracellular catalytic domain of β-secretase has from 8th International Conference on Alzheimer's Disease Drug Discovery New York, NY, USA. 15–16 October 2007 Published: 3 December 2008 BMC Neuroscience 2008, 9(Suppl 2):S4 doi:10.1186/1471-2202-9-S2-S4 Proceedings of the 8th International Conference on Alzheimer's Disease Drug Discovery Howard Fillit The publication of this supplement was made possible by the generous support of the conference sponsors: Forest Laboratories, Inc.; Bellus Health Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; Esai, Inc., Ortho-McNeil Neurologics, Inc.; Sanofi-Aventis US, Inc.; Schering-Plough; Accera, Inc.; Acumen Pharmaceuticals, Inc.; Pfizer Inc.; and Wyeth Research. Reviews http:// www.biomedcentral.com/content/pdf/1471-2202-9-S2-info.pdf This article is available from: http://www.biomedcentral.com/1471-2202/9/S2/S4 © 2008 Wolfe; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
منابع مشابه
Cyclooxygenase-2 inhibition improves amyloid-beta-mediated suppression of memory and synaptic plasticity.
Non-steroidal anti-inflammatory agents (NSAIDs) are associated with a marked reduction in the risk of developing Alzheimer's disease, a form of dementia characterized by the accumulation of amyloid plaques containing the amyloid-beta protein (Abeta). Studies of the effects of NSAIDs upon the inflammatory response surrounding amyloid plaques and upon the generation of Abeta from the amyloid prec...
متن کاملAnti-inflammatory drug therapy alters beta-amyloid processing and deposition in an animal model of Alzheimer's disease.
Alzheimer's disease (AD) is characterized by a microglial-mediated inflammatory response elicited by extensive amyloid deposition in the brain. Nonsteroidal anti-inflammatory drug (NSAID) treatment reduces AD risk, slows disease progression, and reduces microglial activation; however, the basis of these effects is unknown. We report that treatment of 11-month-old Tg2576 mice overexpressing huma...
متن کاملDoes Long-Term Administration of a Beta-Blocker (Timolol) Induce Fibril-Based Cataract Formation In-vivo?
Timolol is a non-selective beta-adrenergic receptor antagonist administered for treating glaucoma, heart attacks and hypertension. In the present study, we set out to determine whether or not timolol can provoke cataract formation, thus the influence of timolol on the amyloid-type aggregation of crystallin was investigated. We then provided experimental evidence of crystallin aggregation and it...
متن کاملLowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model
beta-amyloid levels are elevated in Down syndrome (DS) patients throughout life and are believed to cause Alzheimer's disease (AD) in adult members of this population. However, it is not known if beta-amyloid contributes to intellectual disability in younger individuals. We used a gamma-secretase inhibitor to lower beta-amyloid levels in young mice that model DS. This treatment corrected learni...
متن کاملDoes Long-Term Administration of a Beta-Blocker (Timolol) Induce Fibril-Based Cataract Formation In-vivo?
Timolol is a non-selective beta-adrenergic receptor antagonist administered for treating glaucoma, heart attacks and hypertension. In the present study, we set out to determine whether or not timolol can provoke cataract formation, thus the influence of timolol on the amyloid-type aggregation of crystallin was investigated. We then provided experimental evidence of crystallin aggregation and it...
متن کاملThe experimental Alzheimer's disease drug posiphen [(+)-phenserine] lowers amyloid-beta peptide levels in cell culture and mice.
Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid beta-peptide (Abeta), a proteolytic fragment of amyloid beta precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe Abeta-lowering drugs. A selective acetyl...
متن کامل