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Licensed Unlicensed Requires Authentication Published by De Gruyter May 1, 2013

Genetic and Pharmacological Basis for Therapeutic Inhibition of Band γ-Secretases in Mouse Models of Alzheimer's Memory Deficits

Masuo Ohno EMAIL logo


Alzheimer's disease (AD) is a dementing neurodegenerative disorder for which effective disease-modifying therapeutic treatments have not yet been developed. Genetic and molecular biological studies provide accumulating evidence supporting the hypothesis that the production of amyloid-ß (Aß) peptides, especially neurotoxic Aß42, is central to the pathophysiology of AD - the 'amyloid cascade' hypothesis. Aß is proteolytically generated from a type I integral membrane amyloid precursor protein by the sequential action of two enzymes, called β- and γ-secretase, in reference to their cleavage sites at the N- and C-terminals, respectively. Given the strong association between Aß and AD, the strategies to inhibit the production of Aß, the first step of the amyloid cascade, should prove beneficial as truly disease-modifying therapeutic approaches for the treatment of AD. Recent advances in genetic strategies including knockouts, transgenics and virus-delivered small interfering RNAs and the development of potent and specific small-molecule inhibitors have opened a new window to test the impacts of β- and γ-secretase inhibition in vivo. Since cognitive deficits are at the heart of AD, one of the most important challenges is to determine the therapeutic potential of secretase-inhibiting approaches for AD-related memory deficits, linking perspectives through the prism of molecular/pathological events and those through behavioral and neurophysiological manifestations. I review recent progress in this field, with special focus on the functional consequences of β- and γ-secretase inhibition and altered amyloid neuropathology in mouse models of AD memory deficits.

Published Online: 2013-05-01
Published in Print: 2006-08

© 2013 by Walter de Gruyter GmbH & Co.

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