Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 24, Issue 4, Pages 669-679Publisher
IOS PRESS
DOI: 10.3233/JAD-2011-101512
Keywords
Angiotensin I/II; angiotensinogen; cholesterol; 24-hydroxycholesterol; mild cognitive impairment; neurodegeneration
Categories
Funding
- Swedish Brain Power
- Riskbankens jubileumsfond
- Gun och Bertil Stohnes Stiftelse
- Karolinska Institutet fund for geriatric research
- Stiftelsen Gamla Tjanarinnor
- Swedish Research Council
- Alzheimerfonden
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In spite of the fact that cholesterol does not pass the blood-brain barrier (BBB), hypercholesterolemia has been linked to increased Alzheimer's disease (AD) risk. Hypertension is another risk factor and angiotensin converting enzyme (ACE) activity is known to be increased in AD. Furthermore, a lower incidence of AD has been reported in patients taking anti-hypertensive drugs. Here we show that the levels of angiotensinogen (AGT) and ACE are increased in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and AD. Moreover, we show ACE activity in the CSF to be positively correlated with both plasma and CSF levels of 27-hydroxycholesterol (27-OH), an oxysterol known to pass through the BBB and taken up from the circulation by the brain. In addition, treatment of rat primary neurons, astrocytes, and human neuroblastoma cells with 27-OH resulted in increased production of AGT. Our results demonstrate that upregulation of renin-angiotensin system (RAS) in AD brains occurs not only at the enzymatic level (ACE) but also at the substrate level (AGT). The possibility that 27-OH is part of a mechanism linking hypercholesterolemia with increased brain RAS activity and increased AD risk is discussed.
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