Insulin-Resistant Brain State after Intracerebroventricular Streptozotocin Injection Exacerbates Alzheimer-like Changes in Tg2576 AβPP-Overexpressing Mice

Article type: Research Article

Authors: Plaschke, Konstanze^{a; *} | Kopitz, Juergen^b | Siegelin, Markus^c | Schliebs, Reinhard^d | Salkovic-Petrisic, Melita^e | Riederer, Peter^f | Hoyer, Siegfried^b

Affiliations: [a] Clinic of Anesthesiology, University of Heidelberg Medical School, Heidelberg, Germany | [b] Department of Pathology, University of Heidelberg, Heidelberg, Germany | [c] Department of Neuropathology, University of Heidelberg, Heidelberg, Germany | [d] Paul-Flechsig Institute for Brain Research; Neurochemistry, University of Leipzig, Germany | [e] Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia | [f] Clinical Neurochemistry, National Parkinson Foundation Centre of Excellence Research Laboratory, Clinic and Policlinic for Psychiatry, Psychosomatic and Psychotherapy, University Hospital of Wuerzburg, Germany

Correspondence: [*] Corresponding author: Konstanze Plaschke, M.D., Ph.D., Department of Anesthesiology, Im Neuenheimer Feld 110, D-69120 Heidelberg, Germany. Tel.: +49 6221 566451; Fax: +49 6221 564399; E-mail: [email protected].

Abstract: For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-β protein precursor (AβPP) followed by increased amyloid-β (Aβ) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS). We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK)α/β content, and the formation of AD-like morphological hallmarks Aβ and tau protein in AβPP Tg2576 mice. Nine-month-old Tg mice were investigated 6 months after a single icv injection of STZ or placebo. Spatial cognition was analyzed using the Morris water maze test. Soluble and aggregated Aβ40/42 fragments, total and phosphorylated tau protein, and GSK-3α/β were determined by ELISA. Cerebral (immuno)histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated Aβ fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3α/β ratio (phosphorylated/total). A linear negative correlation was detected between Aβ42 and cognition, and between GSK-3α/β ratio and aggregated Aβ40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3α/β pathway in AβPP-overexpressing mice.

Keywords: Amyloid-β, glycogen synthase kinase-3, insulin, sporadic Alzheimer's disease, streptozotocin, transgenic 2576 mice, tau

DOI: 10.3233/JAD-2010-1270

Journal: Journal of Alzheimer's Disease, vol. 19, no. 2, pp. 691-704, 2010