Blockade of α4 integrins reduces leukocyte–endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer’s disease

Pietronigro, Enrica Caterina; Zenaro, Elena; Bianca, Vittorina Della; Dusi, Silvia; Terrabuio, Eleonora; Iannoto, Giulia; Slanzi, Anna; Ghasemi, Somayehsadat; Nagarajan, Rajasekar; Piacentino, Gennj; Tosadori, Gabriele; Rossi, Barbara; Constantin, Gabriela

doi:10.1038/s41598-019-48538-x

Cited by 52 publications

(35 citation statements)

References 60 publications

(84 reference statements)

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“…Adhering leukocytes stall blood flow in capillaries [91]. And adhesion molecule expression and BBB impairment facilitate the recruitment of leukocytes to the brain [152,153,204,205]. When inflammatory cytokines and chemokines reach the brain parenchyma, they can be neurotoxic [206], and spur local inflammation by activation of microglia and astrocytes [170,172].…”

Section: Vascular Inflammationmentioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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Background: Cerebrovascular disease is a common comorbidity in patients with Alzheimer's disease (AD). It is believed to contribute additively to the cognitive impairment and to lower the threshold for the development of dementia. However, accumulating evidence suggests that dysfunction of the cerebral vasculature and AD neuropathology interact in multiple ways. Vascular processes even proceed AD neuropathology, implicating a causal role in the etiology of AD. Thus, the review aims to provide an integrated view on vascular dysfunction in AD. Summary: In AD, the cerebral vasculature undergoes pronounced cellular, morphological and structural changes, which alters regulation of blood flow, vascular fluid dynamics and vessel integrity. Stiffening of central blood vessels lead to transmission of excessive pulsatile energy to the brain microvasculature, causing endorgan damage. Moreover, a dysregulated hemostasis and chronic vascular inflammation further impede vascular function, where its mediators interact synergistically. Changes of the cerebral vasculature are triggered and driven by systemic vascular abnormalities that are part of aging, and which can be accelerated and aggravated by cardiovascular diseas-es. Key Messages: In AD, the cerebral vasculature is the locus where multiple pathogenic processes converge and contribute to cognitive impairment. Understanding the molecular mechanism and pathophysiology of vascular dysfunction in AD and use of vascular blood-based and imaging biomarker in clinical studies may hold promise for future prevention and therapy of the disease.

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Section: Vascular Inflammationmentioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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“…For example, mouse models of AD have increased endothelia/leucocyte interactions due to increased inflammation and the presence of neutrophil extracellular traps. ( 73–75 ). Ultimately, this chronic vascular inflammation could directly increase the number of capillary stalls and impact CBF.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model

Falkenhain

et al. 2021

Preprint

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Increased incidence of stalled capillary blood flow caused by adhesion of leucocytes to the brain microvascular endothelium leads to a 17% reduction of cerebral blood flow (CBF) and exacerbates short-term memory loss in multiple mouse models of Alzheimers disease (AD). Here, we report that Vascular Endothelial Growth Factor (VEGF) signaling at the luminal side of the brain microvasculature plays an integral role in the capillary stalling phenomenon of the APP/PS1 mouse model. Administration of the anti-mouse VEGF-A164 antibody, an isoform that inhibits blood brain barrier (BBB) hyperpermeability, reduced the number of stalled capillaries within an hour of injection, leading to an immediate increase in average capillary blood flow but not capillary diameter. VEGF-A inhibition also reduced the overall eNOS protein concentrations, increased occludin levels, and decreased the penetration of circulating Evans Blue dye across the BBB into the brain parenchyma, suggesting increased BBB integrity. Capillaries prone to neutrophil adhesion after anti-VEGF-A treatment also had lower occludin concentrations than flowing capillaries. Taken together, our findings demonstrate that VEGF-A signaling in APP/PS1 mice contributes to aberrant eNOS/occludin- associated BBB permeability, increases the incidence of capillary stalls, and leads to reductions in CBF. Reducing leucocyte adhesion by inhibiting luminal VEGF signaling may provide a novel and well-tolerated strategy for improving brain microvascular blood flow in AD patients.

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“…The transmigration is reported to be protein kinase C dependent [61]. VLA4 have been shown to mediate leukocyte-endothelial interactions in cerebral vessels, blockade of which was shown to improve memory in an AD mouse model [62]; however, this paper did not focus specifically on monocytes.…”

Section: Alzheimer's Diseasementioning

confidence: 96%

The Roles of Monocyte and Monocyte-Derived Macrophages in Common Brain Disorders

Zhao

Tuo

Wang

et al. 2020

BioMed Research International

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The brain is the most important and complex organ in most living creatures which serves as the center of the nervous system. The function of human brain includes controlling of the motion of the body and different organs and maintaining basic homeostasis. The disorders of the brain caused by a variety of reasons often severely impact the patients’ normal life or lead to death in extreme cases. Monocyte is an important immune cell which is often recruited to the brain in a number of brain disorders. However, the role of monocytes may not be simply described as beneficial or detrimental. It significantly depends on the disease models and the stages of disease progression. In this review, we summarized the current knowledge about the role of monocytes and monocyte-derived macrophages during several common brain disorders. Major focuses include ischemic stroke, Alzheimer’s disease, multiple sclerosis, intracerebral hemorrhage, and insomnia. The recruitment, differentiation, and function of monocyte in these diseases are reviewed.

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Blockade of α4 integrins reduces leukocyte–endothelial interactions in cerebral vessels and improves memory in a mouse model of Alzheimer’s disease

Cited by 52 publications

References 60 publications

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Inhibition of peripheral VEGF signaling rapidly reduces leucocyte obstructions in brain capillaries and increases cortical blood flow in an Alzheimer’s disease mouse model

The Roles of Monocyte and Monocyte-Derived Macrophages in Common Brain Disorders

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