Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

Koizumi, Kenzo; Wang, Gang; Park, Laibaik

doi:10.1007/s10571-015-0256-9

Cited by 107 publications

(96 citation statements)

References 109 publications

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“…The brain is highly dependent on a continuous and well-regulated delivery of cerebral blood flow (CBF), and alterations in cerebral perfusion lead to brain dysfunction and cognitive impairment 11–13 . A large body of work indicates that Aβ disrupts key mechanisms regulating the cerebral microcirculation 13–15 . For example, Aβ suppresses the increase in CBF evoked by synaptic activity, a vital homeostatic response that matches oxygen and glucose delivery to the energy needs of the active brain, and disrupts endothelial function 16–21 .…”

Section: Introductionmentioning

confidence: 99%

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Park

Uekawa

García-Bonilla

et al. 2017

Circulation Research

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Rationale Increasing evidence indicates that alterations of the cerebral microcirculation may play a role in Alzheimer’s disease (AD), the leading cause of late-life dementia. The amyloid-β peptide (Aβ), a key pathogenic factor in AD, induces profound alterations in neurovascular regulation through the innate immunity receptor CD36, which, in turn, activates a Nox2-containing NADPH oxidase leading to cerebrovascular oxidative stress. Brain perivascular macrophages (PVM) located in the perivascular space, a major site of brain Aβ collection and clearance, are juxtaposed to the wall of intracerebral resistance vessels and are a powerful source of reactive oxygen species (ROS). Objective We tested the hypothesis that PVM are the main source of ROS responsible for the cerebrovascular actions of Aβ, and that CD36 and Nox2 in PVM are the molecular substrates of the effect. Methods and Results Selective depletion of PVM using intracerebroventricular injection of clodronate abrogates the ROS production and cerebrovascular dysfunction induced by Aβ applied directly to the cerebral cortex, administered intravascularly or overproduced in the brain of transgenic mice expressing mutated forms of the amyloid precursor protein (Tg2576 mice). In addition, using bone marrow chimeras we demonstrate that PVM are the cells expressing CD36 and Nox2 responsible for the dysfunction. Thus, deletion of CD36 or Nox2 from PVM abrogates the deleterious vascular effects of Aβ, whereas wild-type PVM reconstitute the vascular dysfunction in CD36-null mice. Conclusions The data identify PVM as a previously unrecognized effector of the damaging neurovascular actions of Aβ and unveil a new mechanism by which brain-resident innate immune cells and their receptors may contribute to the pathobiology of AD.

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Section: Introductionmentioning

confidence: 99%

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Park

Uekawa

García-Bonilla

et al. 2017

Circulation Research

Self Cite

175

213

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“…This therapeutic approach receives added impetus from continual findings of cerebrovascular pathology (Beishon et al 2017;Goldwaser et al 2016;Hishikawa et al 2016;Kapasi and Schneider 2016;Kelleher and Soiza 2013;Malojcic et al 2017;McAleese et al 2016;Muche et al 2017;Nelson et al 2016;Nielsen et al 2017;Noh et al 2016;Perrotta et al 2016;Raz et al 2016;Weekman et al 2016) and brain arterial aging (Calabrese et al 2016;Cooper and Mitchell 2016;Gutierrez et al 2016;Kelleher and Soiza 2013;Malojcic et al 2017;Nagata et al 2016;Raz et al 2016;Toth et al 2017) accompanying Alzheimer's disease. Similarly, there is an apparent endothelium-dysfunction involvement Bhat 2015;Carradori et al 2016;Chao et al 2016;Devraj et al 2016;Di Marco et al 2015;Festoff et al 2016;Gangoda et al 2016;Hishikawa et al 2016;Hostenbach et al 2016;Kahlil et al 2016;Kelleher and Soiza 2013;Koizumi at al. 2016;Koster et al 2016;Muche et al 2017;Qosa et al 2016;Roberts et al 2016;Salmina et al 2010;Shang et al 2016;) in Alzheimer's dis...…”

Section: Targeted Delivery (Of Drugs Including Antibody Therapeutics)mentioning

confidence: 99%

“…Accordingly, endothelial modulation and repair become feasible by pharmacological targeting (Carradori et al 2016;Di Marco et al 2015;Hostenbach et al 2016;Koizumi at al. 2016;Koster et al 2016;Qosa et al 2016;Salmina et al 2010;Tong and Hamel 2015;Zenaro et al 2016) via SR-BI receptors (cf.…”

Section: Targeted Delivery (Of Drugs Including Antibody Therapeutics)mentioning

confidence: 99%

Nanotherapy for Early Dementia: Targeting Senile Dementia

D'Arrigo¹

2017

Preprint

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Due to the complexity of Alzheimer's disease, multiple cellular types need to be targeted simultaneously in order for a given therapy to demonstrate any major effectiveness. Ultrasound-sensitive coated microbubbles (in a targeted lipid nanoemulsion) are available. Versatile small molecule drug(s) targeting multiple pathways of Alzheimer's disease pathogenesis are known. By incorporating such drug(s) into the targeted LCM/ND lipid nanoemulsion type, one obtains a multitasking combination therapeutic for translational medicine. This multitasking therapeutic targets cell-surface scavenger receptors (mainly SR-BI), making possible for various Alzheimer's-related cell types to be simultaneously searched out for localized drug treatment in vivo. Besides targeting cell-surface SR-BI, the proposed LCM/ND-nanoemulsion combination therapeutic(s) include a characteristic lipid-coated microbubble [LCM] subpopulation (i.e., a stable LCM suspension); such filmstabilized microbubbles are well known to substantially reduce the acoustic power levels needed for accomplishing temporary noninvasive (transcranial) ultrasound treatment, or sonoporation, if additionally desired for the Alzheimer's patient.

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“…Moreover, endothelial cell aging likely increases their susceptibility to toxic effects of Aβ (Brandes et al, 2005). This toxicity occurs via stimulation of cell death pathways involving caspase-3 and caspase-8, TNF-related-apoptosis-inducing-ligand (Ghiso et al, 2014; Xu et al, 2001), ASK1-JNK/p38 apoptotic signaling pathways (Hsu et al, 2007), death receptors DR4 and DR5 (Ghiso et al, 2014), oxidative stress pathways, and intracellular calcium ion overload (Koizumi et al, 2016). Additional pathways involve altered endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production (Suhara et al, 2003), and disruption of vascular proliferation (Grammas et al, 1995), potentially through effects on vascular endothelial growth receptor (Patel et al, 2010).…”

Section: Neurovascular Unit and The Tbi-ad Linkmentioning

confidence: 99%

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders

Ikonomović

Abrahamson

2017

Ageing Research Reviews

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Traumatic brain injury (TBI), advanced age, and cerebral vascular disease are factors conferring increased risk for late onset Alzheimer’s disease (AD). These conditions are also related pathologically through multiple interacting mechanisms. The hallmark pathology of AD consists of pathological aggregates of amyloid-β (Aβ) peptides and tau proteins. These molecules are also involved in neuropathology of several other chronic neurodegenerative diseases, and are under intense investigation in the aftermath of TBI as potential contributors to the risk for developing AD and chronic traumatic encephalopathy (CTE). The pathology of TBI is complex and dependent on injury severity, age-at-injury, and length of time between injury and neuropathological evaluation. In addition, the mechanisms influencing pathology and recovery after TBI likely involve genetic/epigenetic factors as well as additional disorders or comorbid states related to age and central and peripheral vascular health. In this regard, dysfunction of the aging neurovascular system could be an important link between TBI and chronic neurodegenerative diseases, either as a precipitating event or related to accumulation of AD-like pathology which is amplified in the context of aging. Thus with advanced age and vascular dysfunction, TBI can trigger self-propagating cycles of neuronal injury, pathological protein aggregation, and synaptic loss resulting in chronic neurodegenerative disease. In this review we discuss evidence supporting TBI and aging as dual, interacting risk factors for AD, and the role of Aβ and cerebral vascular dysfunction in this relationship. Evidence is discussed that Aβ is involved in cyto- and synapto-toxicity after severe TBI, and that its chronic effects are potentiated by aging and impaired cerebral vascular function. From a therapeutic perspective, we emphasize that in the fields of TBI- and aging-related neurodegeneration protective strategies should include preservation of neurovascular function.

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Endothelial Dysfunction and Amyloid-β-Induced Neurovascular Alterations

Cited by 107 publications

References 109 publications

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Brain Perivascular Macrophages Initiate the Neurovascular Dysfunction of Alzheimer Aβ Peptides

Nanotherapy for Early Dementia: Targeting Senile Dementia

Disordered APP metabolism and neurovasculature in trauma and aging: Combined risks for chronic neurodegenerative disorders

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