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

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 ß 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.

Depressive-like behaviors in a rat model of chronic cerebral hypoperfusion.

The vascular depression hypothesis suggests that there is an association between cerebrovascular pathophysiology and depression in the elderly. We investigated depressive-like behaviors and perturbations in the hypothalamus-pituitary-adrenal (HPA) axis in a rat model of chronic cerebral hypoperfusion. We modeled chronic cerebral hypoperfusion by permanent occlusion of the bilateral common carotid arteries (BCCAo) in Wistar rats. Sucrose preference, forced swim, and social interaction tests were performed to measure depressive-like behaviors. The plasma levels of adrenocorticotropic hormone and corticosterone, and the hippocampal expression of the glucocorticoid receptor (GR) were assessed. Sucrose preference (P = 0.045) and social withdrawal (P = 0.038) were significantly enhanced in BCCAo rats. Increased plasma levels of corticosterone (P = 0.034) and impaired cytosolic-to-nuclear translocation of the GR protein were observed in the hippocampus (P = 0.038) of BCCAo rats. Our experimental results support the clinical hypothesis that vascular depression can be induced by chronic cerebral hypoperfusion. Increased HPA axis activity and perturbation of the GR signaling pathway in the hippocampus may be associated with depressive-like behaviors in rats with chronic cerebral hypoperfusion.

NADPH oxidase 1, a novel molecular source of ROS in hippocampal neuronal death in vascular dementia.

AIMS: Chronic cerebral hypoperfusion (CCH) is a common pathological factor that contributes to neurodegenerative diseases such as vascular dementia (VaD). Although oxidative stress has been strongly implicated in the pathogenesis of VaD, the molecular mechanism underlying the selective vulnerability of hippocampal neurons to oxidative damage remains unknown. We assessed whether the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) complex, a specialized superoxide generation system, plays a role in VaD by permanent ligation of bilateral common carotid arteries in rats. RESULTS: Male Wistar rats (10 weeks of age) were subjected to bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]). Nox1 expression gradually increased in hippocampal neurons, starting at 1 week after 2VO and for approximately 15 weeks after 2VO. The levels of superoxide, DNA oxidation, and neuronal death in the CA1 subfield of the hippocampus, as well as consequential cognitive impairment, were increased in 2VO rats. Both inhibition of Nox by apocynin, a putative Nox inhibitor, and adeno-associated virus-mediated Nox1 knockdown significantly reduced 2VO-induced reactive oxygen species generation, oxidative DNA damage, hippocampal neuronal degeneration, and cognitive impairment. INNOVATION AND CONCLUSION: We provided evidence that neuronal Nox1 is activated in the hippocampus under CCH, causing oxidative stress and consequential hippocampal neuronal death and cognitive impairment. This evidence implies that Nox1-mediated oxidative stress plays an important role in neuronal cell death and cognitive dysfunction in VaD. Nox1 may serve as a potential therapeutic target for VaD.