Abstract
An abnormal accumulation of cholesterol oxidation products in the brain of patients with Alzheimer’s disease (AD) would further link an impaired cholesterol metabolism in the pathogenesis of the disease. The first evidence stemming from the content of oxysterols in autopsy samples from AD and normal brains points to an increase in both 27-hydroxycholesterol (27-OH) and 24-hydroxycholesterol (24-OH) in the frontal cortex of AD brains, with a trend that appears related to the disease severity. The challenge of differentiated SK-N-BE human neuroblastoma cells with patho-physiologically relevant amounts of 27-OH and 24-OH showed that both oxysterols induce a net synthesis of Aβ1-42 by up-regulating expression levels of amyloid precursor protein and β-secretase, as well as the β-secretase activity. Interestingly, cell pretreatment with N-acetyl-cysteine (NAC) fully prevented the enhancement of β-amyloidogenesis induced by the two oxysterols. The reported findings link an impaired cholesterol oxidative metabolism to an excessive β-amyloidogenesis and point to NAC as an efficient inhibitor of oxysterols-induced Aβ toxic peptide accumulation in the brain.
Highlights
Life expectancy has increased dramatically in most parts of the world over the last forty years but, in parallel, the impact of illness and disability on the aging population has risen significantly
Levels of 27-OH and 24-OH in the frontal cortex of Alzheimer’s disease (AD) brains: upward trend with disease progression A pilot study was done on autopsy samples of frontal cortex from AD brains partly in order to obtain reliable indications concerning the appropriate concentration of 27-OH and 24-OH to use in the in vitro experiments scheduled subsequently
When a distinction was made between early and advanced AD cases, following the classification of Braak and Braak, the steady-state amounts of the two oxysterols recovered from the cerebral frontal cortex might increase with disease progression
Summary
Life expectancy has increased dramatically in most parts of the world over the last forty years but, in parallel, the impact of illness and disability on the aging population has risen significantly. Most research on this point has focused on the ability of cholesterol to modulate amyloidogenesis, i.e. Aβ production, in the brain In this connection, experimental studies carried out far, using cell culture systems and/or animal models, have consistently proved that excess cholesterol may stimulate amyloidogenesis by neuronal cells, and that hypercholesterolemia is associated with increased deposition of Aβ in the brain (for a review see Ricciarelli et al, 2012). Rats fed a cholesterol-rich diet for 5 months showed impaired spatial memory, together with a significant loss of cholinergic neurons These findings were associated with increased levels of APP, Aβ, and phosphorylated tau in the cerebral cortex. This dietary regimen was demonstrated to derange the semi-permeability of the blood-brain barrier (Ehrlich & Humpel, 2012)
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