Effect of amyloid toxicity or chronic cerebral hypoperfusion on brain insulin resistance in a rat model with intracerebroventricular streptozotocin

Abstract

Sporadic Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder affected by amyloid and vascular pathogenesis. Brain insulin resistance (BIR) has been suggested as one of the pathomechanisms of sporadic AD. We investigated how the amyloid and vascular pathogenesis of AD interacts with BIR. We examined experimental groups mimicking amyloid pathogenesis following intracerebroventriculr (icv) injection of amyloid β or vascular pathogenesis following permanent ligation of the bilateral common carotid arteries in Wistar rats that had undergone icv injection of streptozotocin. Behavioral tests and pathologic studies were performed. Cognitive impairments were induced by BIR superimposed by amyloid or vascular pathogenesis. Neuroinflammation in the white matter and hippocampus was aggravated by an interaction between BIR and vascular pathogenesis. Amyloid-associated pathology in the white matter was enhanced by BIR and vascular pathogenesis. Tau-associated pathology in the hippocampus was altered by BIR in a relation with amyloid or vascular pathogenesis. Our study may provide useful experimental insights based on an integrated approach to the influence of amyloid and vascular pathogenesis on BIR, permitting better understanding of the heterogeneous pathogenesis of sporadic AD. Pathologic responses in sporadic AD may differ depending on amyloid and vascular pathogenesis and may sometimes be synergistically aggravated when combined with BIR.

Keywords: Alzheimer’s disease; Amyloid; Chronic cerebral hypoperfusion; Insulin resistance; Neuroinflammation; Streptozotocin.