Modeling Sporadic Alzheimer's Disease: The Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Including Hyperphosphorylated Tau Protein and Amyloid-β

Article type: Review Article

Authors: Salkovic-Petrisic, Melita^{a; *;} | Osmanovic, Jelena^a | Grünblatt, Edna^b | Riederer, Peter^b | Hoyer, Siegfried^c;

Affiliations: [a] Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Croatia | [b] Clinical Neurochemistry Laboratory, National Parkinson Foundation Centre of Excellence Research Laboratory, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University of Würzburg, Würzburg, Germany | [c] Department of Pathology, University of Heidelberg, Heidelberg, Germany

Correspondence: [*] Address for correspondence: Melita Salkovic-Petrisic, Department of Pharmacology & Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Salata 11, HR 10 000 Zagreb, Croatia. Tel.: +385 1 4590 219; Fax: +385 1 4920 049; E-mail: melitas@mef.hr.

Note: [1] These authors contributed equally to this work.

Abstract: Nosologically, Alzheimer's disease (AD) is not a single disorder. Missense gene mutations involved in increased formation of the amyloid-β protein precursor derivatives amyloid-β (Aβ)1-40 and Aβ1-42/43 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 Aβ 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 diseases that only 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 Aβ as abnormal terminal events in sAD rather than causing the disorder, as elaborated in the review.

Keywords: Amyloid-β, brain, hyperphosphorylated tau, insulin, insulin resistant brain state, oxidative metabolism, sporadic Alzheimer disease

DOI: 10.3233/JAD-2009-1184

Journal: Journal of Alzheimer's Disease, vol. 18, no. 4, pp. 729-750, 2009