Intermittent streptozotocin administration induces behavioral and pathological features relevant to Alzheimer's disease and vascular dementia

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Rationale:Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain.Objective and methods:The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia.Results:Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40 mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus.Conclusions:STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.HighlightsIntermittent peripheral streptozotocin induced a sustained hyperglycemic state in an otherwise completely healthy animal.Sustained hyperglycemia resulted in increased inflammatory signaling as well as elevated ptau and learning and memory deficits.The hyperglycemia also induced alterations in insulin and insulin signaling mechanisms, as well as evidence of microvascular hemorrhages.

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