Intracerebroventricular Streptozotocin Exacerbates Alzheimer-Like Changes of 3xTg-AD Mice

Abstract

Alzheimer’s disease (AD) involves several possible molecular mechanisms, including impaired brain insulin signaling and glucose metabolism. To investigate the role of metabolic insults in AD, we injected streptozotocin (STZ), a diabetogenic compound if used in the periphery, into the lateral ventricle of the 6-month old 3xTg-AD mice and studied the cognitive function as well as AD-like brain abnormalities, such as tau phosphorylation and Aβ accumulation, 3–6 weeks later. We found that STZ exacerbated impairment of short-term and spatial reference memory in 3xTg-AD mice. We also observed an increase of tau hyperphosphorylation and neuroinflammation, a disturbance of brain insulin signaling, and a decrease of synaptic plasticity and amyloid β peptides in the brain after STZ treatment. The expression of 20 AD-related genes, including those involved in the processing of amyloid precursor protein, cytoskeleton, glucose metabolism, insulin signaling, synaptic function, protein kinases and apoptosis, was altered, suggesting that STZ disturbs multiple metabolic and cell signaling pathways in the brain. These findings provide experimental evidence of the role of metabolic insult in AD.

Long-term treatment with intranasal insulin ameliorates cognitive impairment, tau hyperphosphorylation, and microglial activation in a streptozotocin-induced Alzheimer’s rat model

“…6a,b). Consistent with our previous studies1718, the levels of phosphorylated AKT (AKT pT308) were substantially upregulated in ICV-STZ rats (Fig. 6a,b).…”

“…3a,b). Consistent with our previous studies18, the inhibitory phosphorylation of GSK-3 at Ser9 (GSK-3β) and Ser21 (GSK-3α) was dramatically upregulated in the hippocampus of ICV-STZ rats. Intranasal insulin reduced the phosphorylation level of GSK-3 in the hippocampus of ICV-STZ rats to that of the control rats (Fig.…”

“…Therefore, in this study, we only investigated the effect of intranasal insulin on tau hyperphosphorylation. Phosphorylation of tau at Ser199/202, Thr205, Ser262, and Ser396 was frequently observed in the brains of ICV-STZ animals in our previous studies and in studies from other groups171819. The phosphorylation of these sites is also required for the conversion of normal tau to pathological tau37.…”

“…Previous studies, including ours, have demonstrated impaired learning and memory in ICV-STZ animals1718. To evaluate whether intranasal insulin ameliorates the cognitive deficits of the ICV-STZ rats, we investigated the spatial reference learning and memory of the rats with a Morris water maze test.…”

Streptozotocin Intracerebroventricular-Induced Neurotoxicity and Brain Insulin Resistance: a Therapeutic Intervention for Treatment of Sporadic Alzheimer’s Disease (sAD)-Like Pathology

“…The STZ-treated animals develop IRBS which is associated with memory impairment, progressive cholinergic deficits, glucose hypometabolism, oxidative stress, and neurodegeneration that share many features in common with sAD in humans. STZ exacerbates AD-like changes which was similar to the 3xTg-AD mice pathophysiology such as processing of APP, glucose metabolism, insulin signaling, synaptic function, protein kinases, and apoptosis [2]. These alterations by STZ suggest that it disturbs multiple metabolic and cell signaling pathways in the brain.…”