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Vol. 3, No. 3, 2006
Issue release date: September 2006
Neurodegenerative Dis 2006;3:134–147
(DOI:10.1159/000094772)

Unraveling in vivo Functions of Amyloid Precursor Protein: Insights from Knockout and Knockdown Studies

Senechal Y. · Larmet Y. · Dev K.K.
aNeuroscience Research, Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; bLaboratoire de Signalisations Moleculaires et Neurodegenerescence, Faculté de Medecine, INSERM, U692, Université Louis-Pasteur, Strasbourg, France

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Abstract

The amyloid precursor protein (APP) is a widely expressed transmembrane protein that is cleaved to generate Aβ peptides in the central nervous system and is a key player in the pathogenesis of Alzheimer’s disease. The precise biological functions of APP still remain unclear although various roles have been proposed. While a commonly accepted model argues that Aβ peptides are the cause of onset and early pathogenesis of Alzheimer’s disease, recent discussions challenge this ‘Aβ hypothesis’ and suggest a direct role for APP in this neurodegenerative disease. Loss-of-function studies are an efficient way to elucidate the role of proteins and concurrently a variety of in vitro and in vivo studies has been performed for APP where protein levels have been downregulated and functional consequences monitored. Complete disruption of APP gene expression has been achieved by the generation of APP knockout animal models. Further knockdown studies using antisense and RNA interference have allowed scientists to reduce APP expression levels and have opened new avenues to explore the physiological roles of APP. In the present review, we focus on knockout and knockdown approaches that have provided insights into the physiological functions of APP and discuss their advantages and drawbacks.



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