Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

Abstract

Increased amyloid beta (AB) peptide concentration is one of the initiating factors in the neurodegeneration process. It has been suggested that cholesterol induces the synthesis of AB peptide from amyloid precursor protein or facilitates the formation of amyloid plaque by lowering the aggregation threshold of the peptide. It is also shown that AB peptides may affect cholesterol metabolism and the synthesis of steroid hormones such as progesterone and estradiol. Pregnenolone (P) and pregnenolone sulfate (PS) are the major steroids produced from cholesterol in neural tissue. In toxicity conditions, the effect of AB peptides on P and PS levels has not yet been determined. Furthermore, it has not been clearly defined how changes in cellular P and PS levels affect neuronal cell survival. The aim of this study was to determine the effects of AB peptides on cellular changes in P and PS levels depending on the level of their main precursor, cholesterol. Cholesterol and toxic concentrations of AB fragments (AB 25-35, AB 1-40 and AB 1-42) were applied to PC-12 and SH-SY5Y cells. Changes in cellular cholesterol, P and PS levels were determined simultaneously in a dose-and time-dependent manner. The cell viability and cell death types were also evaluated. AB peptides affected both cell viability and P/PS levels. Steroid levels were altered depending on AB fragment type and the cholesterol content of the cells. Treatment with each of the AB fragments alone increased P levels by twofold. However, combined treatment with AB peptides and cholesterol increased P levels by approximately sixfold, while PS levels were increased only about 2.5 fold in both cell lines. P levels in the groups treated with AB 25-35 were higher than those in AB 1-40 and AB 1-42 groups. The cell viabilities were significantly low in the group treated by AB and cholesterol (9 mM). The effect of AB peptides on P levels might be a result of cellular self-defense. On the other hand, the rate of P increase might be playing a key role in the cell death mechanism of AB toxicity depending on cellular cholesterol levels.

Metabolic Adaptations in Pregnancy: A Review

“…Studies in premenopausal women administered with the progesterone-only pill have shown marginal reductions in the levels of circulating total cholesterol and triglycerides [45]. However, it has been suggested that the administration of progesterone derivatives is able to blunt the changes in serum lipid profiles due to estrogen [46].…”

Epigallocatechin Gallate Reduces Amyloid β‐Induced Neurotoxicity via Inhibiting Endoplasmic Reticulum Stress‐Mediated Apoptosis

“…The results of the supplementary experiments showed that both Aβ 1-42 and Aβ 1-40 significantly induced decrease in cell viability, and there are no significant differences in cell viability between Aβ 1-40 and Aβ 1-42 treatment (Supporting Information Figure S1A), which is consistent with the previous study. [36] In addition, EGCG treatment also significantly inhibited the expression levels of GRP78, CHOP and cleaved-caspase12 in both Aβ 1-42 -and Aβ 1-40 -induced Figure 5. Effect of EGCG on cleaved-caspase3 expression in the cerebral cortex of APP/PS1 mice.…”

“…As Aβ 1‐40 and Aβ 1‐42 are two of the most common neurotoxic fragments of Aβ peptides and have been widely used in the study of AD, we checked the effects of Aβ 1‐40 as a comparative control in our study. The results of the supplementary experiments showed that both Aβ 1‐42 and Aβ 1‐40 significantly induced decrease in cell viability, and there are no significant differences in cell viability between Aβ 1‐40 and Aβ 1‐42 treatment (Supporting Information Figure S1A), which is consistent with the previous study . In addition, EGCG treatment also significantly inhibited the expression levels of GRP78, CHOP and cleaved‐caspase12 in both Aβ 1‐42 ‐ and Aβ 1‐40 ‐induced SH‐SY5Y cells (Supporting Information Figure S1B–E), suggesting that EGCG protected against both Aβ 1‐42 ‐ and Aβ 1‐40 ‐induced neurotoxicity by attenuating ER stress.…”

Steroids and Alzheimer’s Disease: Changes Associated with Pathology and Therapeutic Potential

“…These reduced PREGS and DHEAS levels suggested that the 3β-HST enzyme involved in their biosynthesis was reduced. However, Calan et al 2016 [ 40 ] showed that toxic doses of Aβ significantly increased PREGS cellular levels in a time-dependent manner in SH-SY5Y cultured cells as compared to control cells ( Figure 2 A). This enhanced steroid production was interpreted as a result of self-defense probably to overcome harmful effects of Aβ.…”

“…In the studies by Marx et al 2006 and Naylor et al 2010 [ 41 , 42 ], high DHEA and PREG concentrations were observed in the prefrontal and temporal cortices of AD patients and tended to be positively correlated with Braak and Braak stage [ 41 ]. Similarly, in SH-SY5Y neuronal cells, treatment with Aβ peptides (Aβ 25–35 , Aβ 1–40 or Aβ 1–42 ) at toxic doses significantly enhanced PREG levels [ 40 ] ( Figure 2 B). PREG levels were higher in the group treated with Aβ 25–35 than the two others and proportionate to cell cholesterol content.…”