Chronic cerebral hypoperfusion shifts the equilibrium of amyloid β oligomers to aggregation-prone species with higher molecular weight

Introduction: This study aimed to evaluate the influence of central angiotensin IV (Ang IV) infusion on chronic cerebral hypoperfusion (CCH)-related neuropathological changes including amyloid-β (Aβ), hyperphosphorylated tau (p-tau) and the inflammatory response. Materials and methods: Rats with CCH received central infusion of Ang IV, its receptor AT4R antagonist divalinal-Ang IV or artificial cerebrospinal fluid for six weeks. During this procedure, the systolic blood pressure (SBP) was monitored, and the levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain were detected. Results: Rats with CCH exhibited higher levels of Aβ42, p-tau and pro-inflammatory cytokines in the brain when compared with controls. Infusion of Ang IV significantly reduced the expression of pro-inflammatory cytokines in the brains of rats with CCH. Meanwhile, the reduction of pro-inflammatory cytokines levels caused by Ang IV was reversed by divalinal-Ang IV. During the treatment, the SBP in rats was not significantly altered. Conclusion: This study demonstrates for the first time that Ang IV dose-dependently suppresses inflammation through AT4R in the brains of rats with CCH, which is independent from SBP. These findings suggest that Ang IV/AT4R may represent a potential therapeutic target for CCH-related neurological diseases.

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Animal Models of Chronic Cerebral Hypoperfusion: From Mouse to Primate

International Journal of Molecular Sciences ◽

10.3390/ijms20246176 ◽

2019 ◽

Vol 20 (24) ◽

pp. 6176 ◽

Cited By ~ 15

Author(s):

Kazuo Washida ◽

Yorito Hattori ◽

Masafumi Ihara

Keyword(s):

White Matter ◽

Animal Models ◽

Mouse Model ◽

Carotid Arteries ◽

Amyloid Β ◽

Chronic Cerebral Hypoperfusion ◽

Motor Dysfunction ◽

Cerebral Hypoperfusion ◽

Left Vertebral Artery ◽

Vessel Occlusion

Vascular cognitive impairment (VCI) or vascular dementia occurs as a result of brain ischemia and represents the second most common type of dementia after Alzheimer’s disease. To explore the underlying mechanisms of VCI, several animal models of chronic cerebral hypoperfusion have been developed in rats, mice, and primates. We established a mouse model of chronic cerebral hypoperfusion by narrowing the bilateral common carotid arteries with microcoils, eventually resulting in hippocampal atrophy. In addition, a mouse model of white matter infarct-related damage with cognitive and motor dysfunction has also been established by asymmetric common carotid artery surgery. Although most experiments studying chronic cerebral hypoperfusion have been performed in rodents because of the ease of handling and greater ethical acceptability, non-human primates appear to represent the best model for the study of VCI, due to their similarities in much larger white matter volume and amyloid β depositions like humans. Therefore, we also recently developed a baboon model of VCI through three-vessel occlusion (both the internal carotid arteries and the left vertebral artery). In this review, several animal models of chronic cerebral hypoperfusion, from mouse to primate, are extensively discussed to aid in better understanding of pathophysiology of VCI.

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Chronic cerebral hypoperfusion: a key mechanism leading to vascular cognitive impairment and dementia. Closing the translational gap between rodent models and human vascular cognitive impairment and dementia

Clinical Science ◽

10.1042/cs20160727 ◽

2017 ◽

Vol 131 (19) ◽

pp. 2451-2468 ◽

Cited By ~ 77

Author(s):

Jessica Duncombe ◽

Akihiro Kitamura ◽

Yoshiki Hase ◽

Masafumi Ihara ◽

Raj N. Kalaria ◽

...

Keyword(s):

Cognitive Impairment ◽

White Matter ◽

Small Vessel Disease ◽

Amyloid Β ◽

Vascular Cognitive Impairment ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Pathophysiological Mechanism ◽

Rodent Models ◽

Recent Refinement

Increasing evidence suggests that vascular risk factors contribute to neurodegeneration, cognitive impairment and dementia. While there is considerable overlap between features of vascular cognitive impairment and dementia (VCID) and Alzheimer’s disease (AD), it appears that cerebral hypoperfusion is the common underlying pathophysiological mechanism which is a major contributor to cognitive decline and degenerative processes leading to dementia. Sustained cerebral hypoperfusion is suggested to be the cause of white matter attenuation, a key feature common to both AD and dementia associated with cerebral small vessel disease (SVD). White matter changes increase the risk for stroke, dementia and disability. A major gap has been the lack of mechanistic insights into the evolution and progress of VCID. However, this gap is closing with the recent refinement of rodent models which replicate chronic cerebral hypoperfusion. In this review, we discuss the relevance and advantages of these models in elucidating the pathogenesis of VCID and explore the interplay between hypoperfusion and the deposition of amyloid β (Aβ) protein, as it relates to AD. We use examples of our recent investigations to illustrate the utility of the model in preclinical testing of candidate drugs and lifestyle factors. We propose that the use of such models is necessary for tackling the urgently needed translational gap from preclinical models to clinical treatments.

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The Effect of Chronic Cerebral Hypoperfusion on Amyloid-β Metabolism in a Transgenic Mouse Model of Alzheimer’s Disease (PS1V97L)

Journal of Alzheimer s Disease ◽

10.3233/jad-171094 ◽

2018 ◽

Vol 62 (4) ◽

pp. 1609-1621 ◽

Cited By ~ 6

Author(s):

Heyun Yang ◽

Tingting Hou ◽

Wei Wang ◽

Yumin Luo ◽

Feng Yan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Transgenic Mouse ◽

Amyloid Β ◽

Transgenic Mouse Model ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Model Of Alzheimer’S Disease

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Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse

Brain Research ◽

10.1016/j.brainres.2019.146379 ◽

2019 ◽

Vol 1723 ◽

pp. 146379 ◽

Cited By ~ 3

Author(s):

Jingwei Shang ◽

Toru Yamashita ◽

Feng Tian ◽

Xianghong Li ◽

Xia Liu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Blood Vessels ◽

Disease Model ◽

Amyloid Β ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Model Mouse ◽

Related Proteins

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The Influence of Chronic Cerebral Hypoperfusion on Cognitive Function and Amyloid β Metabolism in APP Overexpressing Mice

PLoS ONE ◽

10.1371/journal.pone.0016567 ◽

2011 ◽

Vol 6 (1) ◽

pp. e16567 ◽

Cited By ~ 48

Author(s):

Mahito Yamada ◽

Masafumi Ihara ◽

Yoko Okamoto ◽

Takakuni Maki ◽

Kazuo Washida ◽

...

Keyword(s):

Cognitive Function ◽

Amyloid Β ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion

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Chronic cerebral hypoperfusion alters amyloid-β peptide pools leading to cerebral amyloid angiopathy, microinfarcts and haemorrhages in Tg-SwDI mice

Clinical Science ◽

10.1042/cs20170962 ◽

2017 ◽

Vol 131 (16) ◽

pp. 2109-2123 ◽

Cited By ~ 10

Author(s):

Natalia Salvadores ◽

James L. Searcy ◽

Philip R. Holland ◽

Karen Horsburgh

Keyword(s):

Amyloid Β ◽

Chronic Cerebral Hypoperfusion ◽

Cerebral Hypoperfusion ◽

Amyloid Angiopathy ◽

Amyloid Β Peptide ◽

Wild Type ◽

Aβ Peptides ◽

Bilateral Carotid ◽

The Brain ◽

Bilateral Carotid Artery

Cerebral hypoperfusion is an early feature of Alzheimer’s disease (AD) that influences the progression from mild cognitive impairment to dementia. Understanding the mechanism is of critical importance in the search for new effective therapies. We hypothesized that cerebral hypoperfusion promotes the accumulation of amyloid-β (Aβ) and degenerative changes in the brain and is a potential mechanism contributing to development of dementia. To address this, we studied the effects of chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis on Aβ peptide pools in a transgenic mouse model of AD (transgenic mice with Swedish, Dutch and Iowa mutations in human amyloid precursor protein (APP) (Tg-SwDI)). Cerebrovascular integrity was characterized by quantifying the occurrence of microinfarcts and haemorrhages and compared with wild-type mice without Aβ. A significant increase in soluble Aβ peptides (Aβ40/42) was detected after 1 month of hypoperfusion in the parenchyma in parallel with elevated APP and APP proteolytic products. Following 3 months, a significant increase in insoluble Aβ40/42 was determined in the parenchyma and vasculature. Microinfarct load was significantly increased in the Tg-SwDI as compared with wild-type mice and further exacerbated by hypoperfusion at 1 and 3 months. In addition, the number of Tg-SwDI hypoperfused mice with haemorrhages was increased compared with hypoperfused wild-type mice. Soluble parenchymal Aβ was associated with elevated NADPH oxidase-2 (NOX2) which was exacerbated by 1-month hypoperfusion. We suggest that in response to hypoperfusion, increased Aβ production/deposition may contribute to degenerative processes by triggering oxidative stress promoting cerebrovascular disruption and the development of microinfarcts.

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