Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer's disease

Abstract

The cascade of Alzheimer's disease (AD) neurodegeneration is associated with persistent oxidative stress, mitochondrial dysfunction, impaired energy metabolism, and activation of pro-death signaling pathways. More recently, studies with human postmortem brain tissue linked many of the characteristic molecular and pathological features of AD to reduced expression of the insulin and insulin-like growth factor (IGF) genes and their corresponding receptors. We now demonstrate using an in vivo model of intracerebral Streptozotocin (ic-STZ), that chemical depletion of insulin and IGF signaling mechanisms combined with oxidative injury is sufficient to cause AD-type neurodegeneration. The ic-STZ-injected rats did not have elevated blood glucose levels, and pancreatic architecture and insulin immunoreactivity were similar to control, yet their brains were reduced in size and exhibited neurodegeneration associated with cell loss, gliosis, and increased immunoreactivity for p53, actived glycogen synthase kinase 3β, phospho-tau, ubiquitin, and amyloid-β. Real time quantitative RT-PCR studies demonstrated that the ic-STZ-treated brains had significantly reduced expression of genes corresponding to neurons, oligodendroglia, and choline acetyltransferase, and increased expression of genes encoding glial fibrillary acidic protein, microglia-specific proteins, acetylcholinesterase, tau, and amyloid precursor protein. These abnormalities were associated reduced expression of genes encoding insulin, IGF-II, insulin receptor, IGF-I receptor, and insulin receptor substrate-1, and reduced ligand binding to the insulin and IGF-II receptors. These results demonstrate that many of the characteristic features of AD-type neurodegeneration can be produced experimentally by selectively impairing insulin/IGF functions together with increasing oxidative stress, and support our hypothesis that AD represents a neuro-endocrine disorder associated with brain-specific perturbations in insulin and IGF signaling mechanisms, i.e. Type 3 diabetes.

What have we learned from the streptozotocin-induced animal model of sporadic Alzheimer’s disease, about the therapeutic strategies in Alzheimer’s research

“…Supporting the hypothesis that the pathophysiology in the STZ-icv animal models shares huge similarities with the one in AD patients, cholinergic deficits have also been consistently found in various STZ-icv animal AD models (from newborn and adult rats to adult mice treated with STZ-icv), by demonstrating as a decrease in ChAT and an increase in AChE activity in the hippocampus, respectively (Hellweg et al 1992;Blokland and Jolles 1993;Blokland and Jolles 1994;Prickaerts et al 1999;Terwel et al 1995;Sonkusare et al 2005;Ishrat et al 2006;(Lester-Coll et al 2006; de la Monte et al 2006;Kumar et al 2010;Tota et al 2011). Importantly, AChE inhibitors tested so far, have been consistently successful in improving/preventing memory deficits in STZ-icv sAD models.…”

“…The PPAR agonist-induced effect has been explored also in the 3-day-old rat pups given STZ-icv injection (40 µg/kg) and on the same day treated with a single ip injection of saline or PPAR α/δ/γ agonists with memory evaluation and brain analysis being done 4 weeks after the drug treatment (de la Monte et al 2006). PPAR agonist treatments showed responses in range from being inefficient to partially or completely rescuing the brains from STZ-mediated neurodegeneration.…”

“…Following the parenteral administration of high doses, STZ selectively destroys insulin producing/secreting β cells in the pancreas, causing DM type I in adult animals (Szkudelski 2001), while multiple parenteral treatment with low to moderate STZ doses causes insulin resistance by damaging insulin receptor (IR) signalling (Blondel and Portha 1989;Kadowaki et al 1984;Giorgino et al 1992). Intracerebroventricular administration of low, subdiabetogenic doses of STZ has been shown to induce cognitive (Mayer et al 1991;Lannert and Hoyer 1998) and brain cholinergic deficits (Hellweg et al 1992;Blockland andJolles 1993, 1994), oxidative stress (Sharma and Gupta, 2001a;Sharma and Gupta 2002;Ishrat et al 2006;Pathan et al 2006;Shoham et al, 2006;Kumar et al, 2010;Saxena et al, 2011) as well as decrement in brain glucose/energy metabolism (Nitsch and Hoyer 1991;Plaschke et al 1996;Lannert and Hoyer 1998;Hoyer and Lannert 2007), and insulin resistant brain state (Salkovic-Petrisic et al 2006;Gruenblatt et al 2007;Steen 2006;Lester-Coll et al 2006;Agrawal et al 2010). These STZ-icv induced effects have been extensively reviewed elsewhere Salkovic-Petrisic et al 2012), and will not be elaborated here.…”

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

“…Disturbances in central insulin signaling have also been shown to affect amyloid-beta (Ab) levels and tau protein hyperphosphorylation (Hoyer, 2004;Salkovic-Petrisic et al, 2009), supporting the notion that sAD may be considered to be the brain type of diabetes (Hoyerm 2002;. 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).…”

Curcumin ameliorates impaired insulin/IGF signalling and memory deficit in a streptozotocin-treated rat model

“…The majority of AD patients are late onset (sporadic) and the disease usually develops after 65 years of age. Sporadic AD (SAD) is associated with peripheral insulin abnormalities, which might influence cerebral glucose metabolism in the brain (Lester-Coll et al 2006). De Santi et al demonstrated the hypometabolism of hippocampal glucose in patients with AD compared to control individuals (De Santi et al 2001), and hypothesised that reduced glucose utilisation and energy metabolism may be two of the main causes of the impaired cognition observed in AD (Rivera et al 2005).…”