Insulin/IGF Signaling-Related Gene Expression in the Brain of a Sporadic Alzheimer's Disease Monkey Model Induced by Intracerebroventricular Injection of Streptozotocin

Abstract

We reported previously that the intracerebroventricular streptozotocin (icv-STZ)-treated cynomolgus monkey showed regionally specific glucose hypometabolism in FDG-PET imaging, similar to that observed in the early stages of sporadic Alzheimer's disease (sAD). However, further pathological analyses of this model at the molecular level are needed to validate it as a feasible model for sAD. Two cynomolgus monkeys were injected with 2 mg/kg STZ into the cerebellomedullary cistern at day 1, 7 and 14. Two control monkeys were given normal saline. At 5 months after injection, the expression levels of genes encoding 9 upstream molecules in insulin/insulin-like growth factor (IGF) signaling and markers for 4 cell-type populations in the frontal cortex, hippocampus, posterior cingulate, precuneus, and occipital cortex of control and icv-STZ treated cynomolgus monkeys were examined. Real-time quantitative PCR analyses demonstrated that the overall mRNA expression of insulin/IGF signaling-related genes was mainly impaired in the anterior part of the cerebrum, frontal cortex, and hippocampus, similar to the early stage of sAD. The changes were accompanied by the loss of oligodendrocytes and neurons. The posterior part of the cerebrum did not show degenerative alterations. The present study provides important fundamental information on the icv-STZ monkey model for sAD. These results may help guide future studies using this model for the investigation of pathological mechanisms and the development of drugs for sAD.

Nine-month follow-up of the insulin receptor signalling cascade in the brain of streptozotocin rat model of sporadic Alzheimer’s disease

“…Streptozotocin (STZ) is a drug toxic for insulin secreting/producing cells and IR (Szkudelski 2001, Kadowaki et al 1984. Similar to what has been found in the human sAD brain, the glucose metabolism was found reduced in 17 of 35 brain areas in the STZ-icv treated rats (Duelli et al 1994) and the activities of glycolytic key enzymes were found markedly decreased (Plaschke and Hoyer 1993) Recently, regionally specific glucose hypometabolism in FDG-PET imaging was found in monkeys 6 and 12 weeks after the STZ-icv treatment (Lee et al 2014;Heo et al 2011). Numerous changes have been found in the insulin/IR signalling cascade in the brain of STZ animal model as reviewed in Table 1.…”

“…The progression of decrement in IR protein expression correlated with downregulation of the corresponding gene up to the 3-month time-point after which a magnitude of decrement in the protein level started slowly but persistently to decline in the course of time. Some reports indicate downregulation of IR mRNA in HPC observed as long as 5 months after the STZ-icv treatment (Yang et al 2014;Lee et al 2014) while others (de la did not found significant changes in the HPC 4 weeks after the STZ-icy treatment. The time-course of changes in IDE protein levels in our experiments did not correlate with changes in the corresponding gene as the former did not progressed but showed a tendency of diminishing the magnitude of decrement in a period from 1 to 3 months, after which a persistent decline was observed further on.…”

“…STZ-icv model has additionally been reported to develop also cerebral amyloid angiopathy in rats (appearing at 3 months and progressing up to 9 months after the STZ-icv) (Salkovic-Petrisic 2006;Salkovic-Petrisic 2011) and congophyllic amyloid deposition in mice (1 month after STZ-icv) (Sodhi et al 2013, Wang et al2014 as well as increased hippocampal APP mRNA after 4 weeks in rats (de la ) and normal APP mRNA expression 5 months after STZ-icv treatment in monkeys (Lee et al 2014, Park et al 2013). All were explored in STZ-icv model mostly at one time point only, usually up to 1 or 3 months after the STZ-icv treatment in rats and mice (Agrawal et al 2010, Agrawal et al 2011, Schido et al 2013, Deng et al 2009, Sodhi et al 2013, Wang et al 2014, Chen et al 2013Chen et al2014) and up to 5 months in monkeys (Lee et al 2014;Park et al, 2013;Heo et al 2011). Periods longer than 5 months post-STZ-icv injection have not been explored in regard to the brain insulin system in STZ-icv model of sAD.…”

The diabetic brain and cognition

“…In comparison to AD, in VaD, human brain neurotransmitter alterations are mild, e.g., for choline acetyltransferase activity, muscarinic receptor density, serotonin, dopamine, homovanillic acid, dopamine D1-and D2-receptor density, noradrenaline, and gamma aminobutyric acid (GABA), while 5-hydroxyindoleacetic acid (5-HIAA) shows a more pronounced deficiency. This data summarized here agree in principle with more recent conclusions of post-mortem human brain studies and experimental models (Ohara et al 1994;Pimlott et al 2004;Jia et al 2004;Tohgi et al 1996;Chen et al 2013;Lee et al 2014;Niwa et al 2002;Pedrós et al 2014;Knezovic et al 2015;Barilar et al 2015). CSF concentrations of choline were significantly higher in VaD patients compared to AD and controls but did no correlate with mini-mental state examination (MMSE) scores (Jia et al 2004;Tohgi et al 1996).…”

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.…”