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P4‐234: IMPROVED VASCULAR REACTIVITY AND REDUCED CEREBRAL AMYLOID ANGIOPATHY FOLLOWING PASSIVE IMMUNOTHERAPY IN TRANSGENIC MICE
Author(s) -
Bales Kelly,
O'Neill Sharon,
Pozdnyakov Nikolay,
Pan Feng,
Caouette David,
Pi YeQing,
Wood Kathleen M.,
Volfson Dmitri,
Cirrito John,
Han Byung Hee,
Johnson Andrew,
Zipfel Gregory,
Samad Tarek
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.07.006
Subject(s) - cerebral amyloid angiopathy , medicine , pathology , genetically modified mouse , angiopathy , transgene , perivascular space , interstitial fluid , parenchyma , dementia , endocrinology , biology , disease , gene , diabetes mellitus , biochemistry
Background: Mixed brain pathologies account for most dementia cases in community-dwelling older persons and those with multiple brain pathologies, had greatly increased odds (3 fold) for dementia. Cerebrovascular pathology is common in the elderly and contributes to ischemic stroke, intracerebral hemorrhages (ICHs), microbleeds, and cerebral amyloid angiopathy (CAA). Moreover the common co-occurrence of AD and vascular pathology mesh with epidemiologic data showing that many vascular risk factors are also risk factors for brain atrophy and dementia. The importance of vascular dysfunction/degeneration was recognized at the recent NINDS workshop on Alzheimer’s Disease-Related Dementias where several sessions were devoted to the vascular contribution to dementia (May 1-2, 2013). Thus, there is increasing recognition that dysfunction in the cerebral vasculature can play a significant role in dementia, including AD where approximately 80-95% of the cases have cerebral vascular pathology The deposition of amyloid-b (Ab) peptides in the cerebral vasculature is an important component leading to ICH and potentially cognitive impairment in Alzheimer’s disease (AD). Finally, blood pressure lowering was shown to reduce the risk of CAA-related ICH, suggesting that hypertension is a factor in inducing ICH in patients with CAA. Methods: This study aims to determine the effect of Ab accumulation on acute and chronic hypertension using a transgenic mouse model overexpressing mutant human amyloid precursor protein. Tg2576 mice and non-transgenic (nonTg) littermates were treated with an angiontensin II (AngII) infusion with ALZET Osmotic pumps (1000 ng/kg/min) and L-NAME (100 mg/kg/day) in drinking water to produce chronic hypertension. Oneweek later, transient acute hypertension was induced by AngII injections (0.5 m g/g, twice daily). Results: A similar increase in systolic blood pressure was observed in both Tg2576 and nonTg mice, however, compared with nonTg mice, Tg2576 mice developed signs of ICH with a markedly shorter latency. In addition, there was as an increase in CAA in the hypertensive Tg2576 mice and the number and size of spontaneous microhemorrhages were significantly increased. Conclusions: Our mixed vascular brain pathology model, which utilizes APP transgenic mice in combination with an acute and chronic hypertension protocol, significantly increases both cerebrovascular and AD-like pathologies.