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Updated: Jun 6, 2026
07:55
Imaging the Intracellular Trafficking of APP with Photoactivatable GFP
Published on: October 17, 2015
Endothelial nitric oxide modulates expression and processing of amyloid precursor protein
Susan A Austin1, Anantha V Santhanam, Zvonimir S Katusic
1Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, Minn., 55905, USA.
Circulation Research
|December 4, 2010
Summary
Endothelial nitric oxide (NO) plays a key role in regulating amyloid precursor protein (APP) processing. Decreased NO bioavailability increases APP and amyloid-beta levels, suggesting the NO/cGMP pathway as a therapeutic target for Alzheimer disease (AD).
Area of Science:
- Neuroscience
- Cardiovascular Science
- Molecular Biology
Background:
- Sporadic Alzheimer disease (AD) etiology is unclear, but cardiovascular risk factors are linked to increased AD incidence.
- Endothelial dysfunction, specifically reduced nitric oxide (NO) bioavailability, is a common feature linking cardiovascular risk factors to AD.
- The precise relationship between endothelial NO and the mechanisms underlying AD, such as amyloid precursor protein (APP) processing, requires elucidation.
Purpose of the Study:
- To investigate the role of endothelial-derived NO in modulating the expression and processing of amyloid precursor protein (APP).
- To determine the impact of NO bioavailability on the production of amyloid-beta (Aβ) peptides, a key component of AD pathology.
Main Methods:
- Utilized human brain microvascular endothelial cells to study NO's effect on APP expression and processing in vitro.
- Inhibited endothelial nitric oxide synthase (eNOS) using L-NAME to assess changes in APP, BACE1, and Aβ levels.
- Examined APP and BACE1 expression, BACE1 activity, and Aβ levels in brain and cerebral microvessels of eNOS-deficient (eNOS(-/-)) mice compared to wild-type controls.
Main Results:
- Inhibition of eNOS in vitro significantly increased APP and BACE1 protein levels and amyloid-beta (Aβ) secretion.
- Brain tissue from eNOS(-/-) mice exhibited significantly higher APP and BACE1 protein levels compared to wild-type controls.
- eNOS deficiency in mice led to increased BACE1 enzyme activity and elevated levels of Aβ, alongside higher BACE1 protein in cerebral microvessels.
Conclusions:
- Endothelial NO significantly modulates APP expression and processing within the brain and cerebrovasculature.
- The findings highlight the NO/cGMP pathway as a potential therapeutic target for preventing and treating mild cognitive impairment and AD.
- Restoring NO bioavailability may offer a novel strategy to mitigate AD pathogenesis by influencing APP processing and Aβ production.
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