Synergistic Memory Impairment Through the Interaction of Chronic Cerebral Hypoperfusion and Amlyloid Toxicity in a Rat Model

Abstract

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 ...

Characterization of White Matter Injury in a Rat Model of Chronic Cerebral Hypoperfusion

“…Consistent with previous studies, 7 we confirmed the presence of memory impairments using the water maze task and novel object test in a rat model of chronic cerebral hypoperfusion. Poor performance in the odor discrimination task suggests that cognitive functions associated with olfaction were also impaired in a rat model of chronic cerebral hypoperfusion.…”

“…6 For chronic cerebral hypoperfusion, rats subjected to permanent occlusion of the bilateral common carotid arteries (BCCAo) were used, which has been previously suggested as a possible animal model for vascular dementia. 7,8 As time went on after the surgery, cerebral blood flow and metabolism decreased chronically in our previous study 7 ( Figure I in the online-only Data Supplement). In this study, we investigated cognitive impairment and its association with disintegration of diverse white matter components.…”

“…3 In previous studies, neuroinflammation has been suggested as a key pathophysiology of white matter injury in animal models of chronic cerebral hypoperfusion. 5,7,8 The loss of oligodendrocytes or compromised oligodendrogenesis has been reported in a mouse model of cerebral hypoperfusion. 12,13 In our study, the loss of oligodendrocytes, attenuation of myelin density, and concomitant neuroinflammation were prominent.…”

Cardiovascular risk in cognitively preserved elderlies is associated with glucose hypometabolism in the posterior cingulate cortex and precuneus regardless of brain atrophy and apolipoprotein gene variations

“…We also predicted that decreased metabolism in the hippocampal region would be found in proportion to the degree of cardiovascular risk, given both the relevance of this brain region as a critical site of neuropathological AD changes, as well as its particular vulnerability to chronic blood flow deficits in animal models of brain hypoperfusion (Wang et al 2010;Choi et al 2011). Rather unexpectedly, we actually found relatively increased brain metabolism in a voxel cluster located in the parahippocampal gyrus both in the comparisons across three groups and in the high-risk group when compared to the low-risk group.…”

NADPH Oxidase 1, a Novel Molecular Source of ROS in Hippocampal Neuronal Death in Vascular Dementia

“…Since the establishment of two-vessel occlusion (2VO), which is the permanent bilateral occlusion of the common carotid artery, in rats as an animal model to reproduce CCH (51,52), this model has been widely used to study the molecular mechanisms underlying the cognitive impairment, white matter lesions, and neuronal damage observed in CCH, as well as in therapeutic intervention studies (16,34,35,65). Generation and accumulation of amyloid and injury to white matter integrity and glial activation, which result in cognitive impairment, have also been observed in the 2VO rat model (29).…”