Endothelin-1 is Elevated in Alzheimer's Disease and Upregulated by Amyloid-β
Abstract
Vascular dysfunction and lowered cerebral blood flow are thought to contribute to the development and progression of Alzheimer's disease (AD). Endothelin-1 (ET-1) is a potent vasoconstrictor, the production of which is mainly catalyzed by endothelin-converting enzymes (ECEs). We previously showed that ECE-2 is upregulated by amyloid-β (Aβ), and its expression elevated in AD postmortem brain tissue. We have now investigated whether there is a concomitant increase in ET-1. We studied temporal cortex from 20 cases of sporadic AD and 20 matched controls. The cellular distribution of ET-1 was assessed immunohistochemically in paraffin sections. PreproET-1 (EDN1) mRNA and ET-1 protein were measured in homogenates of superior temporal cortex by real-time PCR and sandwich ELISA respectively. Cultured SH-SY5Y human neuroblastoma cells were incubated with 10 μM oligomeric Aβ42 for 24 h, and ET-1 protein level was measured in cell culture supernatants by sandwich ELISA. Antibody to ET-1 labeled neurons throughout the temporal cortex, and the walls of some cerebral blood vessels. ET-1 mRNA measured in the temporal neocortex was significantly elevated in AD when normalized for expression of GAPDH (p = 0.0256) or the neuronal marker neuron-specific enolase (NSE, p = 0.0001). ET-1 protein was also significantly higher in AD than in control tissue, when adjusted for neuronal content by measurement of NSE (p = 0.0275). ET-1 protein in SH-SY5Y cell supernatant rose 1.7-fold after exposure to 10 μM oligomeric Aβ (p = 0.024). These findings provide evidence of overactivity of the endothelin system in AD, further supporting the suggestion that endothelin receptor antagonists may be of value for the treatment of this disease.
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Aβ1−42-evoked generation of ROS is upstream of the elevated level (or potentiated effect) of ET that makes pericytes constrict capillaries.
“These data establish Aβ1−42-evoked generation of ROS as being upstream of the elevated level (30, 31) (or potentiated effect (32)) of ET that makes pericytes constrict capillaries.”
From Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes (2019) · cites this paper as [31]
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- Authors
- Palmer, J. C., Barker, R., Kehoe, P. G., & Love, S.
- Affiliations
- University of Bristol (GB)
- Corresponding author
- Palmer, Jennifer C.
- Venue
- Journal of Alzheimer's Disease
- Publisher
- SAGE Publications
- Published
- 2012-04-16
- Volume
- 29
- Issue
- 4
- Pages
- 853-861
- ISSN
- 1387-2877 (ISSN-L)
- 1875-8908
- OpenAlex
- W2111685488
- Cited by
- 110
- References
- 54
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 7 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 3 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 11 · 2015: 9 · 2014: 10 · 2013: 6 · 2012: 2
- FWCI
- 5.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Alzheimer s Disease (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (submittedVersion)
- Explore Bristol Research (submittedVersion)
- Funders
- British Heart Foundation (PG/10/47/28285)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- endothelin-1, Alzheimer's disease
- MeSH terms
- Endothelin-Converting Enzymes, Aged, Aged, 80 and over, Alzheimer Disease, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Metalloendopeptidases, Middle Aged, Neuroblastoma, Neurons, Peptide Fragments, Phosphopyruvate Hydratase, Postmortem Changes, RNA, Messenger, Temporal Lobe, Up-Regulation, Case-Control Studies, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Endothelin-1, Cell Line, Tumor
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