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

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...

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Detalles Bibliográficos
Autores: Mateos, L. (Laura)|||/items/7c2322e7-5ad1-4e6c-ba36-5eb26ac7c23b, Ismail, M.A. (Muhammad Al-Mustaf)|||/items/f22efba5-aaeb-43b9-ad5c-fd7617c93d77, Gil-Bea, F.J. (Francisco J.)|||/items/33abaa1d-cc6b-4ed9-b0eb-6daa654b1915, Leoni, V. (Valerio)|||/items/9750ebf0-8de8-495c-8593-5d6e1f41897a, Winblad, B. (Bengt)|||/items/66f860b4-fba9-4b01-9422-c8ab1fe9d232, Björkhem, I. (Ingemar)|||/items/c8e99b0e-71c6-462d-82a2-1255f468ae8c, Cedazo-Minguez, A. (Ángel)|||/items/bd0db075-3142-455d-8243-404ccee917b8
Tipo de recurso: artículo
Fecha de publicación:2011
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/19574
Acceso en línea:https://hdl.handle.net/10171/19574
Access Level:acceso abierto
Palabra clave:Angiotensin I/II
angiotensinogen
cholesterol
4-hydroxycholesterol
mild cognitive impairment
neurodegeneration
Descripción
Sumario: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.

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