Abstract
Amyloid peptide, the main component of senile plaques, is a major biological characteristic of Alzheimer’s disease (AD). The aim of the present study conducted on human neuronal SK-N-BE cells was to evaluate whether oligomerized Aβ1-40-induced cell damages was associated with lipid modifications. Under treatment with Aβ1-40 (10 - 100 μM; 24 - 48 h), cell viability was recorded with the MTT test and by measuring LDH activity. Mitochondrial transmembrane potential and ATP production were assessed using flow cytometry and a luciferase-based ATP bioluminescence assay, respectively. Annexin V-CF647 staining assay for cell apoptosis detection was performed using flow cytometry. Potentially intracellular cytotoxic lipids (oxysterols: 7α-hydroxycholesterol (7α-OHC), 7β-hydroxycholesterol (7β-OHC), and 7-ketocholesterol (7KC), 24(S)-hydroxycholesterol; arachidonic acid (C20:4 n-6); VLCFAs (C22:0, C24:0, C24:6 and C26:0)) were measured using gas chromatography coupled with mass spectrometry. The cellular level of docosahexaenoic acid (C22:6 n-3), often altered in AD, was also quantified. In the presence of Aβ1-40, the percentage of MTT-positive cells decreased and was associated with an increase in LDH activity. In addition, treatment with oligomerized Aβ1-40 induced a decrease of mitochondrial transmembrane potential as well as an apoptotic cell death. Sterol analysis revealed a higher cholesterol level and a significant increase of cytotoxic oxysterols per cell (7KC + 7β-OHC), and of the [(7β-OHC + 7KC)/cholesterol] ratio, considered as a lipid peroxidation index, in Aβ1-40-treated cells. An enhancement of C20:4 n-6, C22:6 n-3 and saturated VLCFAs was also observed. Therefore, Aβ1-40-induced side effects are associated with intracellular accumulation of lipids, especially cholesterol, oxysterols (7β-OHC, 7KC), C20:4 n-6, and saturated VLCFAs, which could in turn contribute to neurotoxicity.
Highlights
Alzheimer’s disease (AD) is the most predominant dementia in the elderly
With Aβ1-40 (10-100 μM), as cytotoxic effects in the same range of order were observed with the MTT test, lactate dehydrogenase (LDH) activity was only measured on SK-NBE cells treated with Aβ1-40 (10 μM)
Amyloid peptide (Aβ), the main component of senile plaques, was shown to be neurotoxic in several studies but no data are available to evaluate the relation between this molecule and lipid metabolism disorders associated with AD pathogenesis [7] [14] [18]
Summary
Alzheimer’s disease (AD) is the most predominant dementia in the elderly. Aggregated amyloid deposits are the main components of senile plaques, which are characteristics of the AD brain [1]. Numerous studies support the notion that an alteration of cholesterol metabolism and cholesterol oxide production, 24(S)-hydroxycholesterol (24S-OHC), 27-hydroxycholesterol (27-OHC), 7KC, and 7β-OHC, can play critical roles in degenerative diseases such as AD [3] [4] [6]. Enhanced plasma levels of 24S-OHC, which could be a consequence of neuronal damages, have been reported during the first stages of dementia [12]. Decreased plasma levels of 24S-OHC were reported in other stages and were associated with cerebral atrophy and severity of dementia [13]. It was reported that 24S-OHC downregulates APP trafficking resulting in suppression of Aβ production [15]. 27-OHC enhances production of Aβ1-42 by up-regulating APP and β-secretase [16]
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