Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Okamoto, Yoko; Yamamoto, Toru; Kalaria, Raj N.; Senzaki, Hideto; Maki, Takakuni; Hase, Yoshiki; Kitamura, Akihiro; Washida, Kazuo; Yamada, Mahito; Ito, Hidefumi; Tomimoto, Hidekazu; Takahashi, Ryōsuke; Ihara, Masafumi

doi:10.1007/s00401-011-0925-9

Cited by 217 publications

(220 citation statements)

References 50 publications

(72 reference statements)

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“…In addition, cardiac systolic dysfunction could affect Aβ generation and clearance in the brain as a result of reduced cerebral blood flow [99][100][101][102] . Regional cerebral blood flow and glucose uptake or metabolism are consistently decreased in Aβ-positive patients with AD 103 , and correlate inversely with AD severity 104 .…”

Section: Cardiovascular Diseasementioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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The global burden of Alzheimer disease (AD), already the most common type of dementia, is expected to increase still further owing to population ageing. AD not only causes severe distress for patients and caregivers, but also results in a large economic burden on society. Current major challenges in AD include the lack of reliable biomarkers for its early diagnosis, as well as the lack of effective preventive strategies and treatments 1,2 . Thus, increased understanding of the molecular patho genesis of AD could lead to the development of improved diagnostic and therapeutic strategies.AD is conventionally regarded as a CNS disorder. However, increasing experimental, epidemiological and clinical evidence has suggested that manifestations of AD extend beyond the brain. These systemic alterations might not be simply secondary effects of the cerebral degeneration seen in AD, but could reflect under lying processes linked to progression of the disease. AD pathogenesis is complex, involving abnormal amyloid-β (Aβ) metabolism, tau hyperphosphorylation, oxidative stress, reactive glial and microglial changes, and other pathological events. Given that Aβ is a major hallmark of AD and a fertile area of research in this disease, this Review focuses on the systemic role of Aβ in AD. We discuss the communication between peripheral and central pools of Aβ, and describe interactions between systemic abnormalities and AD pathogenesis in the brain. We review emerging findings of associations between systemic abnormalities and Aβ metabolism, and describe how these associations might interact with or reflect on the central pathways of Aβ production and clearance. On the basis of these findings, we suggest that interactions between the brain and the periphery might have a crucial role in the development and progression of AD. Aβ biogenesis and catabolismA steady accrual of data from laboratories and clinics is providing increasing support for the concept that an imbalance between the production and clearance of Aβ is a very early (and often initiating) factor in AD 3 . Normal metabolism of Aβ and maintenance of the homeostatic balance between Aβ production and clearance is, therefore, essential to maintain brain health. In fact, physiological metabolism of Aβ occurs not only in the brain but also in the periphery, and communication between these regions is possible (FIG. 1). Central and peripheral production of AβAβ is derived from the proteolytic cleavage of amyloid precursor protein (APP), which is expressed not only in brain cells, including neurons, astrocytes and microglia, but also in peripheral organs and tissues, such as the Abstract | Alzheimer disease (AD) is the most common type of dementia, and is currently incurable; existing treatments for AD produce only a modest amelioration of symptoms. Research into this disease has conventionally focused on the CNS. However, several peripheral and systemic abnormalities are now understood to be linked to AD, and our understanding of how these alterations contribute to AD is becom...

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Section: Cardiovascular Diseasementioning

confidence: 99%

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

et al. 2017

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“…39,83 Advanced amyloid deposition in the vessel wall may cause impaired autoregulation, endothelial dysfunction, blood-brain barrier disruption, thickening of the vessel wall, or even vessel occlusion, thereby inducing hypoperfusion and ischemia around the amyloid-laden vessels. 15,57,83,84 Support for this notion comes from experimental studies in mouse models of CAA, demonstrating decreased vascular reactivity in response to physiologic or pharmacologic stimuli compared with wild-type mice. 83,[85][86][87] Furthermore, mice with CAA showed increased susceptibility to induced ischemia, reflected by lower cerebral blood flow and increased infarct volume after middle cerebral artery occlusion.…”

Section: Pathophysiologic Mechanisms Of Ischemia In Cerebral Amyloid mentioning

confidence: 99%

“…Thromboses, atherosclerosis, or arterial stiffening may abolish the motive force necessary for drainage of A through interstitial fluid pathways, which in turn enhances the accumulation of amyloid in the vessel wall. 23,24,57,91 The hypothesis that common age-related vascular diseases, such as atherosclerosis and arterial stiffening, trigger vascular amyloid deposition could also explain the rapid increase in the prevalence of CAA with aging. 3 An imaging marker of impaired clearance of interstitial fluid is dilated perivascular spaces.…”

Section: Pathophysiologic Mechanisms Of Ischemia In Cerebral Amyloid mentioning

confidence: 99%

Ischemic brain injury in cerebral amyloid angiopathy

Reijmer

Veluw

Greenberg

2015

J Cereb Blood Flow Metab

112

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Cerebral amyloid angiopathy (CAA) is a common form of cerebral small vessel disease and an important risk factor for intracerebral hemorrhage and cognitive impairment. While the majority of research has focused on the hemorrhagic manifestation of CAA, its ischemic manifestations appear to have substantial clinical relevance as well. Findings from imaging and pathologic studies indicate that ischemic lesions are common in CAA, including white-matter hyperintensities, microinfarcts, and microstructural tissue abnormalities as detected with diffusion tensor imaging. Furthermore, imaging markers of ischemic disease show a robust association with cognition, independent of age, hemorrhagic lesions, and traditional vascular risk factors. Widespread ischemic tissue injury may affect cognition by disrupting white-matter connectivity, thereby hampering communication between brain regions. Challenges are to identify imaging markers that are able to capture widespread microvascular lesion burden in vivo and to further unravel the etiology of ischemic tissue injury by linking structural magnetic resonance imaging (MRI) abnormalities to their underlying pathophysiology and histopathology. A better understanding of the underlying mechanisms of ischemic brain injury in CAA will be a key step toward new interventions to improve long-term cognitive outcomes for patients with CAA.

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“…White matter damage is detectable with diffusion tensor imaging (DTI) at the early stages of brain injury following CCH (Wang et al, 2015). In addition, cerebral hypoperfusion accelerates cerebral amyloid angiopathy (Okamoto et al, 2012), enhances tau hyperphosphorylation, upregulates β-amyloid precursor protein cleavage enzyme 1 (BACE1) and β-amyloid level in the brain (Zhiyou et al, 2009), the main neuropathological hallmarks of AD.…”

Section: Introductionmentioning

confidence: 99%

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

et al. 2017

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Chronic cerebral hypoperfusion (CCH) evokes mild cognitive impairment (MCI) and contributes to the progression of vascular dementia and Alzheimer's disease (AD). How CCH 2 induces these neurodegenerative processes that may spread along the synaptic network and whether they are detectable at the synaptic proteome level of the cerebral cortex remains to be established.In the present study, we report the synaptic protein changes in the cerebral cortex after stepwise bilateral common carotid artery occlusion (BCCAO) induced CCH in the rat. The occlusions were confirmed with Magnetic Resonance Angiography 5 weeks after the surgery.Synaptosome fractions were prepared using sucrose gradient centrifugation from cerebral cortex dissected 7 weeks after the occlusion. The synaptic protein differences between the sham operated and CCH groups were analysed with label free nanoUHPLC-MS/MS.

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Cerebral hypoperfusion accelerates cerebral amyloid angiopathy and promotes cortical microinfarcts

Cited by 217 publications

References 50 publications

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain

Ischemic brain injury in cerebral amyloid angiopathy

Chronic Cerebral Hypoperfusion Induced Synaptic Proteome Changes in the rat Cerebral Cortex

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