Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway

Casey, Caroline; Atagi, Yuka; Yamazaki, Yu; Shinohara, Mitsuru; Tachibana, Masaya; Fu, Yuan; Bu, Guojun; Kanekiyo, Takahisa

doi:10.1074/jbc.m114.625251

Cited by 54 publications

(41 citation statements)

References 51 publications

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“…For example, one proposal is that apoE4 produced by astrocyte is impaired in its ability to activate the low density lipoprotein receptor-related protein 1 (LRP1) in pericytes, resulting in higher matrix metalloproteinase 9 production, basement membrane degradation and impaired brain endothelial function [33, 42]. In addition, unlike apoE4, apoE3 suppresses pericyte mobility in a pathway involving LRP1 in vitro [43]. Pericyte migration can lead to vessel wall instability, and therefore BBB leakiness.…”

Section: Discussionmentioning

confidence: 99%

Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

Thomas

Morris

Tai

2017

Heliyon

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Cerebrovascular dysfunction is re-emerging as a major component of aging, and may contribute to the risk of developing Alzheimer’s disease (AD). Two important risk factors for cerebrovascular dysfunction are APOE and female sex, which are primarily researched in the context of high amyloid-β (Aβ) levels as found in AD. However, APOE4 and sex modulate Aβ-independent pathways that may induce cerebrovascular dysfunction as a downstream consequence. Therefore, testing the activity of factors that target cerebrovascular dysfunction in Aβ-independent models that incorporate APOE4 and female sex is crucial. We have previously demonstrated that peripheral administration of the epidermal growth factor (EGF) prevents cognitive dysfunction, cerebrovascular leakiness, and cerebrovascular coverage deficits in female mice that express APOE4 and overproduce Aβ, without affecting Aβ levels. These data raise the question of whether EGF protects the cerebrovasculature from general stress-induced damage. Therefore, the goal of this study was to determine whether EGF prevents Aβ-independent cerebrovascular dysfunction. In eight-month old mice that express human APOE, the interaction of APOE4 and female sex induced cognitive dysfunction, increased cerebrovascular leakiness and lowered vessel coverage. Importantly, in a prevention paradigm (from six to eight and a half months of age), EGF ameliorated cognitive decline and cerebrovascular deficits in female mice that express APOE4. Thus, developing treatment strategies based on EGF signaling could provide alternative therapeutic options for age-related cerebrovascular dysfunction and reduce AD risk.

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Section: Discussionmentioning

confidence: 99%

Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

Thomas

Morris

Tai

2017

Heliyon

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“…The brain's HDL-like lipoprotein particles are built around apoE, which is the major lipoprotein expressed, translated, and secreted from astrocytes, microglia, and pericytes across species [36][37][38]39 & ]. Clusterin, also known as apoJ, is also produced from astrocytes but is secreted virtually free of lipids [38,40,41].…”

Section: Brain Lipoproteins and Apolipoproteinsmentioning

confidence: 99%

Relation between plasma and brain lipids

Wellington

Frikke‐Schmidt

2016

Current Opinion in Lipidology

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“…Heparin-bound apoE was eluted with NaCl gradient from 0 to 1 M in Tris buffer. Peak fractions containing pure apoE were concentrated, and quantified by measuring band intensity of silver-stained SDS-PAGE gel against BSA standards or by apoE ELISA (47).…”

Section: Methodsmentioning

confidence: 99%

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

Atagi

Liu

Painter

et al. 2015

Journal of Biological Chemistry

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449

435

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Background: TREM2 is associated with several neurodegenerative diseases. Results: ApoE bound to TREM2 and increased phagocytosis of apoptotic neurons by microglia. Alzheimer disease (AD) risk-associated TREM2-R47H mutant had a reduced binding to apoE. Conclusion: ApoE is a novel ligand for TREM2. Interaction between apoE and TREM2 likely regulates phagocytosis of apoEbound apoptotic neurons. Significance: Interaction between two AD risk-associated proteins modulates microglial function.

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Apolipoprotein E Inhibits Cerebrovascular Pericyte Mobility through a RhoA Protein-mediated Pathway

Cited by 54 publications

References 51 publications

Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

Epidermal growth factor prevents APOE4 -induced cognitive and cerebrovascular deficits in female mice

Relation between plasma and brain lipids

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

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