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APP Transgenic Mouse Models and their Use in Drug Discovery to Evaluate Amyloid-β Lowering Therapeutics

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A critical requirement in the development of Alzheimer's disease (AD) therapeutics is a demonstration of the in vivo efficacy of compounds in pre-clinical disease relevant models. One of the most frequently used models in AD research are transgenic mice overexpressing mutant forms of human amyloid precursor protein (APP) that are associated with early-onset familial AD. These mice exhibit an age-dependent accumulation and deposition of amyloid β-peptide (Aβ) as extracellular plaques in the brain, and thereby depict one of the key pathologies observed in the brains of AD patients. Although these mouse models do not recapitulate all the pathological features of AD, they have been invaluable in the development of therapeutic agents aimed at lowering Aβ production, inhibiting Aβ deposition or facilitating Aβ clearance. Further development of these APP transgenic models led to the incorporation of transgenes for human mutant presenilins, resulting in an accelerated Aβ deposition rate and human mutant tau protein leading to neurofibrillary tangle-like pathology. The latter was a major advance in the development of AD models, as it allowed researchers to investigate the interplay between the two key pathologies of AD. This review highlights how APP transgenic mouse models have successfully been used in drug discovery to support the progression of Aβ lowering therapeutics to clinical trials to ultimately test the 'amyloid hypothesis' of AD.

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Keywords: Alzheimer's disease; Amyloid-β; amyloid precursor protein; presenilin; tau; transgenic mouse

Document Type: Research Article

Affiliations: Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Harlow, Essex, CM19 5AW, UK.

Publication date: 2010-08-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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