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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-29653

Salkovic-Petrisic, M; Osmanovic, J; Grünblatt, E; Riederer, P; Hoyer, S (2009). Modeling sporadic alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities inclusive hyperphosphorylated tau protein and amyloid-beta. A Synthesis. Journal of Alzheimer's Disease, 18(4):729-750.

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Abstract

Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-beta protein precursor derivatives amyloid-beta (Abeta)<formula>_{1-40}</formula> and Abeta<formula>_{1-42/43}</formula> lead to autosomal dominant familial AD, found in the minority of AD cases. However, millions of subjects suffer from sporadic AD (sAD) of late onset, for which no convincing evidence suggests Abeta as the primary disease-generating compound. Environmental factors operating during pregnancy and postnatally may affect susceptibility genes and stress factors (e.g., cortisol), consequently affecting brain development both structurally and functionally, causing disorders becoming manifest late in life. With aging, a desynchronization of biological systems may result, increasing further brain entropy/declining criticality. In sAD, this desynchronization may involve stress components, cortisol and noradrenaline, reactive oxygen species, and membrane damage as major candidates causing an insulin resistant brain state with decreased glucose/energy metabolism. This further leads to a derangement of ATP-dependent cellular and molecular work, of the cell function in general, as well as derangements in the endoplasmic reticulum/Golgi apparatus, axon, synapses, and membranes, in particular. A self-propagating process is thus generated, including the increased formation of hyperphosphorylated tau-protein and Abeta as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review.

Item Type:Journal Article, refereed, further contribution
Communities & Collections:04 Faculty of Medicine > Center for Child and Adolescent Psychiatry
DDC:610 Medicine & health
Language:English
Date:03 August 2009
Deposited On:08 Feb 2010 12:07
Last Modified:27 Nov 2013 21:03
Publisher:IOS Press
ISSN:1387-2877
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.3233/JAD-2009-1184
PubMed ID:19661616
Citations:Web of Science®. Times Cited: 25
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