Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

Merlini, Mario; Rafalski, Victoria A.; Coronado, Pamela E. Rios; Gill, Thomas M; Ellisman, MH; Muthukumar, Gayathri; Subramanian, Keshav S.; Ryu, Jae K.; Syme, Catriona; Davalos, Dimitrios; Seeley, William W.; Mucke, Lennart; Nelson, Robert B.; Akassoglou, Katerina

doi:10.1016/j.neuron.2019.01.014

Cited by 308 publications

(313 citation statements)

References 44 publications

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“…BBB impairment leads to the influx of blood constituents into the central nervous system, impairs clearing mechanism and is associated with rCBF reductions [139]. DOI: 10.1159/000505625 Plasma proteins such as fibrin, thrombin and albumin can directly act on neurons and glia cells, promoting neuronal and axonal damage [146,150], and are activating an immune response [151]. Moreover, BBB impairment facilitates the influx of immune cells as demonstrated by the presence of peripheral macrophages and neutrophils in the central nervous system [152,153].…”

Section: Vascular Integrity In Ad: the Failing Shieldmentioning

confidence: 99%

“…Activated platelets that adhere to the vascular wall release cytokines, growth factors, and numerous pro-inflammatory mediators such as interleukin (IL)-1 and CD40L [168]. Moreover, mediators of the coagulation cascade can extravasate via a leaky BBB and stimulate neuroinflammation by direct interaction with glial cells in the brain parenchyma, stimulating synaptic remodelling and neurodegeneration [150]. Thrombin can activate microglia via protease-activated receptors [169], while fibrinogen has been shown to cause a significant rearrangement of the microglia cytoskeleton and an increase in cell size and phagocytic activity ( Fig.…”

Section: Dysregulated Haemostasismentioning

confidence: 99%

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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 Integrity In Ad: the Failing Shieldmentioning

confidence: 99%

Section: Dysregulated Haemostasismentioning

confidence: 99%

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Klohs

2019

Neurodegener Dis

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“…Growing evidence has demonstrated the considerable interplay between microglia and astrocyte signaling (Liddelow et al, ) and likewise the neuronal regulation of microglia activation state is well‐established (Marinelli, Basilico, Marrone, & Ragozzino, ; Sheridan & Murphy, ). More recently, interactions between vascular endothelial cells and microglia have been implicated in aging, AD, and stroke (Dudvarski Stankovic, Teodorczyk, Ploen, Zipp, & Schmidt, ; Merlini et al, ; Yousef et al, ). Thus, monoculture experiments likely provide only an initial, albeit highly quantitative, assessment of microglial function.…”

Section: Benefits and Limitationsmentioning

confidence: 99%

“…More recently, interactions between vascular endothelial cells and microglia have been implicated in aging, AD, and stroke (Dudvarski Stankovic, Teodorczyk, Ploen, Zipp, & Schmidt, 2016;Merlini et al, 2019;Yousef et al, 2019). Thus, monoculture experiments likely provide only an initial, albeit highly quantitative, assessment of microglial function.…”

Section: In Vitro Imgsmentioning

confidence: 99%

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Hasselmann

Blurton‐Jones

2020

Glia

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Recent advances in the generation of microglia from human induced pluripotent stem cells (iPSCs) have provided exciting new approaches to examine and decipher the biology of microglia. As these techniques continue to evolve to encompass more complex in situ and in vivo paradigms, so too have they begun to yield novel scientific insight into the genetics and function of human microglia. As such, researchers now have access to a toolset comprised of three unique “flavors” of iPSC‐derived microglia: in vitro microglia (iMGs), organoid microglia (oMGs), and xenotransplanted microglia (xMGs). The goal of this review is to discuss the variety of research applications that each of these techniques enables and to highlight recent discoveries that these methods have begun to uncover. By presenting the research paradigms in which each model has been successful, as well as the key benefits and limitations of each approach, it is our hope that this review will help interested researchers to incorporate these techniques into their studies, collectively advancing our understanding of human microglia biology.

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“…Cerebrovascular disease and the associated blood-brain barrier (BBB) dysfunction are intimately associated with immune activation and among the most common age-associated, inflammation-mediated, degenerative brain changes. Vascular pathways are emerging as an important contributor to neurodegenerative disorders [1][2][3][4] . Importantly, immuno-vascular dysregulation can cause pathological systemic-brain cross-talk 5 in early disease states, prior to frank brain degeneration and clinical manifestations such as mild cognitive impairment 6,7 .…”

Section: Introductionmentioning

confidence: 99%

Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

Elahi

Harvey

Altendahl

et al. 2019

Preprint

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We test the hypothesis that endothelial cells take on an inflammatory phenotype in functionally intact human subjects with radiographic evidence of white matter injury. Markers within all three complement effector pathways and regulatory proteins were quantified from endothelial-derived exosomes (EDE) of subjects (age 70-82) with (n=11) and without (n=16) evidence of white matter hyperintensity on MRI. Group differences and associations with systemic markers of immune activation (IL6, ICAM1), cognition and neuroimaging were calculated via regression modelling.EDE complement factors within the alternative and classical pathways were found to be higher and regulatory proteins lower in subjects with WMH. EDE levels of several factors demonstrated significant associations with cognitive slowing and systolic blood pressure. The inhibitor of the membrane attack complex, CD46, showed a significant positive association with cerebral grey matter volume. Systemic inflammatory markers, IL6 and ICAM1, were positively associated with EDE levels of several factors.These findings provide the first in vivo evidence of the association of endothelial cell inflammation with white matter injury, cognition, and brain degeneration in functionally normal older individuals, and form the basis for future biomarker development in early or preclinical stages of vascular cognitive impairment and dementia.

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Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer’s Disease Model

Abstract: Highlights d Fibrinogen is a blood-derived inducer of spine elimination d Fibrinogen promotes synapse loss in AD mice d 3D volume imaging of BBB disruption and Ab in cleared human AD brain d Genetic inhibition of fibrinogen-CD11b binding improves cognition in AD mice

Cited by 308 publications

References 44 publications

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

An Integrated View on Vascular Dysfunction in Alzheimer’s Disease

Human iPSC‐derived microglia: A growing toolset to study the brain's innate immune cells

Endothelial-derived exosomes demonstrate a link between endothelial innate inflammation and brain dysfunction and injury in aging

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