Background and Purpose-Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Methods-Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Results-Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. Conclusions-White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.

Background and Purpose-Vascular pathology and Alzheimer disease (AD) pathology have been shown to coexist in the brains of dementia patients. We investigated how cognitive impairment could be exacerbated in a rat model of combined injury through the interaction of chronic cerebral hypoperfusion and amyloid beta (A␤) toxicity. Methods-In Wistar rats, chronic cerebral hypoperfusion was modeled by permanent occlusion of bilateral common carotid arteries (BCCAo). Further, AD pathology was modeled by bilateral intracerebroventricular A␤ (A␤ toxicity) using a nonphysiological A␤ peptide (A␤ 25 to 35). The experimental animals were divided into 4 groups, including sham, single injury (A␤ toxicity or BCCAo), and combined injury (BCCAo-A␤ toxicity) groups (nϭ7 per group) . Cerebral blood flow and metabolism were measured using small animal positron emission tomography. A Morris water maze task, novel object location and recognition tests, and histological investigation, including neuronal cell death, apoptosis, neuroinflammation, and AD-related pathology, were performed. Results-Spatial memory impairment was synergistically exacerbated in the BCCAo-A␤ toxicity group as compared to the BCCAo or A␤ toxicity groups (PϽ0.05). Compared to the sham group, neuroinflammation with microglial or astroglial activation was increased both in multiple white matter lesions and the hippocampus in other experimental groups. AD-related pathology was enhanced in the BCCAo-A␤ toxicity group compared to the A␤ toxicity group. Conclusion-Our experimental results support a clinical hypothesis of the deleterious interaction between chronic cerebralhypoperfusion and A␤ toxicity. Chronic cerebral hypoperfusion-induced perturbation in the equilibrium of AD-related pathology may exacerbate cognitive impairment in a rat model of combined injury. (Stroke. 2011;42:2595-2604.)Key Words: Alzheimer disease Ⅲ amyloid beta Ⅲ chronic cerebral hypoperfusion Ⅲ Morris water maze Ⅲ vascular dementia A lzheimer disease (AD) and vascular dementia are the most common causes of cognitive decline in the aging population. 1 Accumulation of insoluble amyloid beta (A␤) in the brain has been identified as the major culprit for the cognitive impairment observed in AD patients. 2 Because senile plaques composed of the A␤ peptide have been found in the brains of AD patients, 2 extensive research has focused on the amyloid hypothesis to explain AD pathology.A hypothesis emphasizing the interaction between AD and vascular pathologies has recently emerged. [3][4][5] The Nun study and other clinico-pathological studies 6 -8 have revealed that patients with AD exhibit concomitant vascular lesions in the brain. Further, epidemiological studies have shown that the major risk factors for AD mostly coincide with those for vascular dementia. 4 The Rotterdam study, 9 a large population-based prospective study, reported an increased prevalence of atherosclerosis in patients either with AD or Received March 11, 2011; accepted March 31, 2011 A converging hypothesis involving chronic ...

The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer's disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Aβ) but not with the extracellular APP/Aβ. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

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