Genetic and pharmacological basis for therapeutic inhibition of beta- and gamma-secretases in mouse models of Alzheimer's memory deficits.
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-beta (Abeta) peptides, especially neurotoxic Abeta42, is central to the pathophysiology of AD--the 'amyloid cascade' hypothesis. Abeta is proteolytically generated from a type I integral membrane amyloid precursor protein by the sequential action of two enzymes, called beta- and gamma-secretase, in reference to their cleavage sites at the N- and C-terminals, respectively. Given the strong association between Abeta and AD, the strategies to inhibit the production of Abeta, 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 beta- and gamma-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 beta- and gamma-secretase inhibition and altered amyloid neuropathology in mouse models of AD memory deficits.
Ohno
Masuo
M
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. mohno@nki.rfmh.org
D000544:Alzheimer Disease / Q000235:genetics* / Q000523:psychology*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000502:physiology; D006801:Humans; D008569:Memory Disorders / Q000235:genetics* / Q000523:psychology*; D051379:Mice; D034622:RNA Interference / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse