Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein

Abstract

The intracerebroventricular (icv) application of streptozotocin (STZ) in low dosage was used in 3-month-old rats to explore brain insulin system dysfunction. Three months following STZ icv treatment, the expression of insulin-1 and -2 mRNA was significantly reduced to 11% in hippocampus and to 28% in frontoparietal cerebral cortex, respectively. Insulin receptor (IR) mRNA expression decreased significantly in frontoparietal cerebral cortex and hippocampus (16% and 33% of control). At the protein/activity level, different abnormalities of protein tyrosine kinase activity (increase in hippocampus), total IR b-subunit (decrease in hypothalamus) and phosphorylated IR tyrosine residues (increase) became apparent. The STZ-induced disturbance in learning and memory capacities was not abolished by icv application of glucose transport inhibitors known to prevent STZ-induced diabetes mellitus.The discrepancy between reduced IR gene expression and increase in both phosphorylated IR tyrosine residues/protein tyrosine kinase activity may indicate imbalance between phosphorylation/dephosphorylation of the IR b-subunit causing its dysfunction. These abnormalities may point to a complex brain insulin system dysfunction after STZ icv application, which may lead to an increase in hyperphosphorylated tauprotein concentration. Brain insulin system dysfunction is discussed as possible pathological core in the generation of hyperphosphorylated tau protein as a morphological marker of sporadic Alzheimer's disease.

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

“…IRs play key roles in important neurological processes including learning and memory (26,27) and tau phosphorylation (37,38). Thus, ADDL-induced loss of IRs might represent an important early mechanism underlying memory impairment and other pathological features of AD.…”

Multi-target iron-chelators improve memory loss in a rat model of sporadic Alzheimer's disease

“…Widely exploited transgenic animal models of AD (Lithner et al 2011) represent the familial form of AD and do not mimic the sAD condition (Balducci and Forloni 2011). Animal model which develops insulin resistant brain state and glucose hypometabolism following the intracerebroventricular application of a betacytotoxic drug streptozotocin in small rodents and cynomolgus monkey (STZ-icv model), (Agrawal et al 2011;Grünblatt et al 2007;Lannert and Hoyer 1998;Lee et al 2014;Lester-Coll et al 2006;Plaschke and Hoyer 1993;Salkovic-Petrisic et al 2006), shares similarities with the human sAD condition (Lannert and Hoyer 1998) since insulin resistant brain state was found postmortem in sAD patients (Correia et al 2011;de la Monte and Wands 2005;Frölich et al 1998). Additionally, STZ-icv model demonstrates also cognitive deficits (Mayer et al 1990;Lannert and Hoyer 1998) and decrement in cerebral cholinergic transmission (Blokland and Jolles 1993;Hellweg et al 1992), as well as other features of chronic neurodegeneration like oxidative stress and neuroinflammation (Saxena et al 2011;Sharma and Gupta 2001) and in particular tau protein hyperphosphorylation (Grünblatt et al 2007;Deng et al 2009;Liu et al 2014;Peng et al 2013), pathological Aβ accumulation (Shingo et al 2013) and cerebral amyloid angiopathy (Salkovic-Petrisic et al 2006, 2011.…”

Chronic nicotine attenuates behavioral and synaptic plasticity impairments in a streptozotocin model of Alzheimer’s disease

“…The intracerebroventricular (icv) administration of the diabetes-inducing drug streptozotocin (icv-STZ) has been investigated as a non-transgenic model of sAD (Lester-Coll et al, 2006;Salkovic-Petrisic and Hoyer, 2007). Subdiabetogenic doses of icv-STZ (1-3 mg/kg) mimic features of human sAD, such as metabolic dysfunctions (Hoyer and Lannert, 2007), brain insulin resistance associated with tau protein hyperphosphorylation (Gru¨nblatt et al, 2007;Barilar et al, 2015), Ab-like aggregation in meningeal vessels (Salkovic-Petrisic et al, 2011), cholinergic deficits (Blokland and Jolles, 1993), and memory impairments (Lannert and Hoyer, 1998;Agrawal et al, 2011). Taking into consideration that STZ does not cross the blood-brain barrier, icv-STZ decrease cerebral glucose uptake without altering blood glucose level (Grieb, 2016).…”