title: Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer's disease.
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.
authors.affiliation: Department of Neurobiology, Care Sciences and Society, Karolinska Institutet-Alzheimer's Disease Research Center, NOVUM, Stockholm, Sweden. Laura.Mateos-Montejo@ki.se
authors.forename: Laura
authors.initials: L
authors.lastname: Mateos
authors.forename: Muhammad-Al-Mustafa
authors.initials: MA
authors.lastname: Ismail
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gil-Bea
authors.forename: Valerio
authors.initials: V
authors.lastname: Leoni
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Angel
authors.initials: A
authors.lastname: Cedazo-Mínguez
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology*; D000808:Angiotensinogen / Q000096:biosynthesis / Q000502:physiology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D060825:Cognitive Dysfunction / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D007703:Peptidyl-Dipeptidase A / Q000096:biosynthesis / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D015415:Biomarkers; D006888:Hydroxycholesterols; D000808:Angiotensinogen; C076996:27-hydroxycholesterol; D007703:Peptidyl-Dipeptidase A