Hypertension enhances A β -induced neurovascular dysfunction, promotes β -secretase activity, and leads to amyloidogenic processing of APP
Open accessAbstract
Hypertension (HTN) doubles the risk of Alzheimer’s disease (AD), but the mechanisms remain unclear. Amyloid- β (A β), a key pathogenic factor in AD, induces cerebrovascular dysfunction. We hypothesized that HTN acts in concert with A β to amplify its deleterious cerebrovascular effects and to increase A β production. Infusion of angiotensin II (ANGII; intravenously) elevated blood pressure and attenuated the cerebral blood flow (CBF) response to whisker stimulation or the endothelium-dependent vasodilator acetylcholine (ACh) ( P < 0.05). Neocortical application of A β in mice receiving ANGII worsened the responses to ACh ( P < 0.05). The cerebrovascular dysfunction observed in Tg2576 mice, in which A β is elevated both in blood and in brain due to expression of mutated amyloid precursor protein (APP), was not aggravated by neocortical application of ANGII or by a 2-week administration of ‘slow pressor’ of ANGII (600 ng/kg per minute; subcutaneously). In contrast, ANGII aggravated the dysfunction in TgSwDI mice, in which A β is increased only in brain. Slow-pressor ANGII induced microvascular amyloid deposition in Tg2576 mice and enhanced β-secretase APP cleavage. In Chinese hamster ovary (CHO) cells producing A β, ANGII increased β-secretase activity, A β1–42, and the A β42/40 ratio. We conclude that HTN enhances amyloidogenic APP processing, effects that may contribute to the pathogenic interaction between HTN and AD.
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Vascular risk factors including hypertension, diabetes, hyperlipidemia, and cardiovascular disease, as well as environment and lifestyle, all affect cerebrovascular and BBB dysfunction.
“Vascular risk factors including hypertension (169, 272), diabetes (43, 110), hyperlipidemia (74), and cardiovascular disease (594), as well as environment (e.g., pollution) (87-89, 207) and lifestyle (e.g., obesity, sedentary lifestyle) (281, 643) all affect cerebrovascular and BBB dysfunction (429, 571), and may influence onset and progression of AD.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [169]
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- Authors
- Faraco, G., Park, L., Zhou, P., Luo, W., Paul, S. M., Anrather, J., & Iadecola, C.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Iadecola, Costantino
- ORCID
- Venue
- Journal of Cerebral Blood Flow & Metabolism
- Publisher
- SAGE Publications
- Published
- 2015-04-29
- Volume
- 36
- Issue
- 1
- Pages
- 241-252
- ISSN
- 0271-678X (ISSN-L)
- 1559-7016
- PMC
- PMC4758560
- OpenAlex
- W2049909061
- Semantic Scholar
- 97aad74a411a6629e1247dd1f1a94b531d315a39
- Cited by
- 158
- References
- 40
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 19 · 2023: 14 · 2022: 11 · 2021: 17 · 2020: 13 · 2019: 23 · 2018: 14 · 2017: 11 · 2016: 16 · 2015: 3
- FWCI
- 10.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cerebral Blood Flow & Metabolism (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p01hl096571-05)
- National Heart, Lung, and Blood Institute (P01-HL96571)
- National Institute of Neurological Disorders and Stroke (R37-NS89323, R37NS089323, R01NS037853, R01-NS37853)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- hypertension, Alzheimer's disease, amyloid-beta, angiotensin II, cerebrovascular dysfunction, cerebral blood flow, acetylcholine, beta-secretase, APP processing, amyloid deposition, Aβ42/Aβ40 ratio, Tg2576 mice
- MeSH terms
- Alzheimer Disease, Angiotensin II, Animals, Blood Pressure, Cerebrovascular Circulation, Cricetulus, Disease Models, Animal, Hypertension, Male, Mice, Inbred C57BL, Mice, Transgenic, Amyloid beta-Peptides, CHO Cells, Amyloid beta-Protein Precursor, Cerebral Amyloid Angiopathy, Amyloid Precursor Protein Secretases
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