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- W2012334054 abstract "Cholesterol metabolism disruptions have been associated with neurodegenerative diseases such as Alzheimer's disease (AD) and hypertension, a risk factor for AD as well. The brain being autonomous in its cholesterol metabolism from the periphery, via the function of the blood brain barrier (BBB), raises the paradox of how plasma cholesterol can cause the effects seen in these disorders. Metabolites of cholesterol permeable to the BBB such as 27-hydroxycholesterol (27-OH) and 24(S)-hydroxycholesterol (24S-OH) are observed to have altered levels in AD. Additionally, we have previously reported, increased angiotensin-converting enzyme (ACE) activity and angiotensinogen (AGT) levels in the CSF of both mild cognitive impairment and AD patients, where a positive correlation between ACE activity and both plasma and CSF levels of 27-OH was also observed. To further understand this intricate relationship and how oxysterols affect the brain renin-angiotensin system (RAS), we scrutinized several models using RT-PCR and immunoblotting. Mice fed a cholesterol-enriched diet exhibited an upregulation of ACE, AGT and JAK/STAT activity in the brain. This enhancement of the brain RAS was confirmed in neuronal and astrocytal rat primary cultures treated with the oxysterols and extending further downstream to increase the levels of ACE2 and Mas receptor mediated partially by liver X receptors. Investigating the brain RAS activity in cyp27a1 -deficient mice, a model of reduced 27-OH production from cholesterol revealed a decrease in the levels of AGT and JAK/STAT activity. Moreover, normocholesterolemic patients with elevated levels of 27-OH due to a CYP7B1 mutation had markers of RAS activation in the CSF. Overall, our results indicate the modulatory effects oxysterols are exerting on the brain RAS partially through a LXR dependent mechanism, augmenting the notion that these cholesterol metabolites are more than just bystanders, but display a metabolically active role. While taking into account the correlation of cholesterol and 27-OH in the circulation and the permeability of 27-OH into the brain, we suggest that disturbances in these cholesterol metabolites could be a mechanistic link connecting hypercholesterolemia, hyptertension and neurodegeneration." @default.
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- W2012334054 date "2012-07-01" @default.
- W2012334054 modified "2023-10-02" @default.
- W2012334054 title "P3-061: Oxysterol-mediated activation of brain renin-angiotensin system: A molecular link with hypertension and Alzheimer's disease" @default.
- W2012334054 doi "https://doi.org/10.1016/j.jalz.2012.05.1280" @default.
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