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

For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (A beta PP) followed by increased amyloid-beta (A beta) 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) alpha/beta content, and the formation of AD-like morphological hallmarks A beta and tau protein in A beta PP 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 A beta(40/42) fragments, total and phosphorylated tau protein, and GSK-3 alpha/beta were determined by ELISA. Cerebral (immuno) histological analyses were performed. In Tg mice, STZ treatment increased mortality, reduced spatial cognition, and increased cerebral aggregated A beta fragments, total tau protein, and congophilic amyloid deposits. These changes were associated with decreased GSK-3 alpha/beta ratio (phosphorylated/total). A linear negative correlation was detected between A beta(42) and cognition, and between GSK-3 alpha/beta ratio and aggregated A beta(40+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-3 alpha/beta pathway in A beta PP-overexpressing mice.