Abstract
Intracerebroventricular administration (ICV) of streptozotocin (STZ) in rats has been associated to desensitization of the insulin receptor (IR) and biochemical changes similar to those occurring in Alzheimer’s disease (AD) or older brains, so it has been proposed as a suitable model for studying some of the pathological features of AD sporadic type (SAD). In this study, we investigated the role of glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A) in the regulation of the phosphorylation of tau (p-tau). Results showed that ICV-STZ treated rats had deficits in short- (1.5-h) and long-term (24- and 48-h) memory after one month of ICV-STZ treatment and six months relative to control rats. The memory deficit was associated to increasing [F(3, 12) = 31.48, p < 0.0001] p-tau in the hippocampus but not in prefrontal cortex (PFC). Likewise, STZ reduced phosphorylation of GSK3β (p-GSK3β) and PP2A in hippocampus and PFC, indicating that GSK3β and PP2A contributed to regulation of p-tau. These data supporting the model with ICV-STZ in rat are adequate to study the progressive memory impairment associated to hyperphosphorylation of tau and the cascade of insulin receptor signaling; confirm that phosphatidyl-inositol-3 kinase-protein kinase B (PI3K-PKB/Akt-GSK3β) and PP2A are involved in the modulation of proteins responsible for the regulation of neurodegeneration in AD.
Highlights
Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by progressive memory loss and a gradual decline in cognitive function, eventually leading to premature death of the individual, which occurs typically 3 - 9 years after diagnosis [1]
These data supporting the model with Intracerebroventricular administration (ICV)-STZ in rat are adequate to study the progressive memory impairment associated to hyperphosphorylation of tau and the cascade of insulin receptor signaling; confirm that phosphatidyl-inositol-3 kinase-protein kinase B (PI3K-PKB/AktGSK3β) and phosphatase 2A (PP2A) are involved in the modulation of proteins responsible for the regulation of neurodegeneration in AD
The present study found short-term memory (STM) and long-term memory (LTM), and progressive memory impairment following one and six months of icv STZ injection, respectively
Summary
Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by progressive memory loss and a gradual decline in cognitive function, eventually leading to premature death of the individual, which occurs typically 3 - 9 years after diagnosis [1]. The ICV administration of low STZ doses (1 3 mg/kg) reproduces aspects of SAD abnormalities, including decreased glucose utilization in rat cortical regions and hippocampus [24] [25] [26] [27], cholinergic deficits [25], increase in oxidative stress [28] [29] [30], decrease of IR expression and hyperphosphorylated tau protein in the hippocampus [31], and amyloid formation in leptomeningeal vessels [30] All these changes are associated to memory impairment, and tau pathology, resulting in central insulin dysfunction [30] [31] [32] [33]. We are testing that ICV-STZ animal model provides key information about the role of brain insulin disruption in AD pathology, studying the effect at six months following icv STZ administration on memory function, phosphorylated levels of tau and GSK3β, and PP2A levels
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