Mouse models of Alzheimer's disease cause rarefaction of pial collaterals and increased severity of ischemic stroke.

Content Provider	Europe PMC
Author	Zhang, Hua Jin, Bo Faber, James E.
Abstract	Vascular dysfunction contributes to the progression and severity of Alzheimer’s disease (AD). Patients with AD also sustain larger infarctions after ischemic stroke; however, the responsible mechanisms are unknown. Pial collaterals are the primary source of protection in stroke. Unfortunately, natural aging and other vascular risk factors cause a decline in collateral number and diameter (rarefaction) and an increase in stroke severity. Herein, we tested the hypothesis that AD accelerates age-induced collateral rarefaction and examined potential underlying mechanisms. Triple and double transgenic mouse models of AD both sustained collateral rarefaction by 8 months of age, well before the onset of rarefaction caused by aging alone (16 months of age). Rarefaction, which did not progress further at 18 months of age, was accompanied by a twofold increase in infarct volume after MCA occlusion. AD did not induce rarefaction of similarly sized pial arterioles or penetrating arterioles. Rarefaction was minimal and occurred only at 18 months of age in a parenchymal vascular amyloid-beta model of AD. Rarefaction was not associated with amyloid-beta deposition on collaterals or pial arteries, nor was plaque burden or CD11b+ cell density greater in brain underlying the collateral zones versus elsewhere. However, rarefaction was accompanied by increased markers of oxidative stress, inflammation, and aging of collateral endothelial and mural cells. Moreover, rarefaction was lessened by deletion of CX3CR1 and prevented by overexpression of eNOS. These findings demonstrate that mouse models of AD promote rarefaction of pial collaterals and implicate inflammation-induced accelerated aging of collateral wall cells. Strategies that reduce vascular inflammation and/or increase nitric oxide may preserve collateral function.Electronic supplementary materialThe online version of this article (10.1007/s10456-018-9655-0) contains supplementary material, which is available to authorized users.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC6475514&blobtype=pdf
ISSN	09696970
Journal	Angiogenesis
Volume Number	22
DOI	10.1007/s10456-018-9655-0
PubMed Central reference number	PMC6475514
Issue Number	2
PubMed reference number	30519973
e-ISSN	15737209
Language	English
Publisher	Springer Netherlands
Publisher Date	2018-12-05
Publisher Place	Dordrecht
Access Restriction	Open
Rights License	Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. © The Author(s) 2018
Subject Keyword	Collateral circulation Alzheimer’s disease Cerebral amyloid angiopathy Stroke
Content Type	Text
Resource Type	Article
Subject	Physiology Clinical Biochemistry Cancer Research