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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is remarkably characterized by pathological hallmarks which include amyloid plaques, neurofibrillary tangles, neuronal loss, and progressive cognitive loss. Several well-known genetic mutations which are being used for the development of a transgenic model of AD lead to an early onset familial AD (fAD)-like condition. However, these settings are only reasons for a small percentage of the total AD cases. The large majorities of AD cases are considered as a sporadic in origin and are less influenced by a single mutation of a gene. The etiology of sporadic Alzheimer's disease (sAD) remains unclear, but numerous risk factors have been identified that increase the chance of developing AD. Among these risk factors are insulin desensitization/resistance state, oxidative stress, neuroinflammation, synapse dysfunction, tau hyperphosphorylation, and deposition of Aβ in the brain. Subsequently, these risk factors lead to development of sAD. However, the underlying molecular mechanism is not so clear. Streptozotocin (STZ) produces similar characteristic pathology of sAD such as altered glucose metabolism, insulin signaling, synaptic dysfunction, protein kinases such as protein kinase B/C, glycogen synthase-3β (GSK-3β) activation, tau hyperphosphorylation, Aβ deposition, and neuronal apoptosis. Further, STZ also leads to inhibition of Akt/PKB, insulin receptor (IR) signaling molecule, and insulin resistance in brain. These alterations mediated by STZ can be used to explore the underlying molecular and pathophysiological mechanism of AD (especially sAD) and their therapeutic intervention for drug development against AD pathology.

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

“…The impaired memory of the ICV-STZ rats might be attributed to the loss of functional synapses or subtle changes in both the magnitude and distribution of effective synaptic coupling without causing substantial synapse loss1753. Insulin receptors distribute at synapses and are extremely abundant in areas of rich synaptic density such as the cortex and hippocampus, suggesting a possible relationship between insulin signaling and synaptic plasticity12. In the present study, we found a modest increase in synapsin1, not synaptophysin or PSD-95, in the intranasal insulin treated ICV-STZ rats.…”

“…Rats that received an intracerebroventricular administration of streptozotocin (ICV-STZ), develop several Alzheimer-like pathological changes and behavioral abnormalities, and have been used as a sporadic Alzheimer’s rat model12. More widely known as a diabetogenic substance, STZ causes severe neuronal dysfunction when injected into the brain at a subdiabetogenic dose that does not affect the glucose level in the brain12.…”

“…More widely known as a diabetogenic substance, STZ causes severe neuronal dysfunction when injected into the brain at a subdiabetogenic dose that does not affect the glucose level in the brain12. Single or double ICV-STZ administration chronically decreases cerebral glucose uptake and leads to several AD-like pathophysiological changes such as the progressive deterioration of memory function, brain insulin resistance, decreased brain glucose metabolism, synaptic dysfunction, the accumulation of Aβ, and the hyperphosphorylation of tau1213. The presence of brain insulin resistance and the hyperphosphorylation of tau found in this model makes it very useful for investigating the effects of insulin on tau hyperphosphorylation.…”

Advance of sporadic Alzheimer's disease animal models

“…Moreover, STZ also results in inhibiting Akt/PKB and insulin receptor signaling pathways, and then insulin resistance in the brain. Inhibition of PI3K and AKT also activates the glycogen synthase‐3β which promotes the Aβ accumulation and Tau hyperphosphorylation, in turn, leading to the degeneration of synapse and even neurons . In addition, glucose deficit in the brain could activate the p38 mitogen‐activated protein kinase pathway, cause memory impairments, synapse dysfunction and increase the level of Tau phosphorylation .…”

“…Inhibition of PI3K and AKT also activates the glycogen synthase-3β which promotes the Aβ accumulation and Tau hyperphosphorylation, in turn, leading to the degeneration of synapse and even neurons. 47 In addition, glucose deficit in the brain could activate the p38 mitogen-activated protein kinase pathway, cause memory impairments, synapse dysfunction and increase the level of Tau phosphorylation. 48 On the basis of the observations, scientists have established the sAD animal models induced by STZ.…”