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

• Published in: Angiogenesis (London) Vol. 22; no. 2; pp. 263 - 279
• Main Authors: Zhang, Hua, Jin, Bo, Faber, James E.
• Format: Journal Article
• Language: English
• Published: Dordrecht Springer Netherlands 01.05.2019; Springer Nature B.V
• Subjects: Age; Aging; Aging (artificial); Aging (natural); Aging - genetics; Aging - pathology; Alzheimer Disease - complications; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Protein Precursor - chemistry; Amyloid beta-Protein Precursor - genetics; Animal models; Animals; Arteries; Arterioles; Arterioles - pathology; Biomedical and Life Sciences; Biomedicine; Brain; Brain Ischemia - etiology; Brain Ischemia - pathology; Cancer Research; Cardiology; CD11b antigen; Cell Biology; Cell Count; Cell density; Cerebral blood flow; Cerebral Veins - pathology; Cerebrovascular Circulation - genetics; Clonal deletion; Collateral Circulation - genetics; CX3CR1 protein; Disease Models, Animal; Humans; Inflammation; Ischemia; Mice; Mice, Transgenic; Neovascularization, Physiologic - genetics; Nitric oxide; Occlusion; Oncology; Ophthalmology; Original Paper; Oxidative stress; Pial artery; Presenilin-1 - genetics; Rarefaction; Risk analysis; Risk factors; Rodents; Severity of Illness Index; Stroke; Stroke - etiology; Stroke - pathology; tau Proteins - genetics; Transgenic mice; Collateral circulation; Cerebral amyloid angiopathy; Stroke; Alzheimer’s disease
• ISSN: 0969-6970; 1573-7209
• DOI: 10.1007/s10456-018-9655-0

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 CX 3 CR1 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.