Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease

Laura Mateos, Muhammad Al Mustafa Ismail, Francisco Javier Gil-Bea, Valerio Leoni, Bengt Winblad, Ingemar Björkhem, Angel Cedazo-Mínguez

Research output: Contribution to journalArticlepeer-review

Abstract

In spite of the fact that cholesterol does not pass the blood-brain barrier, hypercholesterolemia has been linked to increase 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.

Original languageEnglish
Pages (from-to)669-679
Number of pages11
JournalJournal of Alzheimer's Disease
Volume24
Issue number4
DOIs
Publication statusPublished - 2011

Keywords

  • 24-hydroxycholesterol
  • Angiotensin I/II
  • angiotensinogen
  • cholesterol
  • mild cognitive impairment
  • neurodegeneration

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology

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