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. 2016 Jan;73(1):201-15.
doi: 10.1007/s00018-015-1988-x. Epub 2015 Jul 22.

Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein

Amandine Grimm  1   2   3 , Emily E Biliouris  1   2 , Undine E Lang  2 , Jürgen Götz  4 , Ayikoe Guy Mensah-Nyagan  3 , Anne Eckert  5   6
Affiliations

Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein

Amandine Grimm et al. Cell Mol Life Sci. 2016 Jan.

Abstract

Alzheimer's disease (AD) is an age-related neurodegenerative disease marked by a progressive cognitive decline. Metabolic impairments are common hallmarks of AD, and amyloid-β (Aβ) peptide and hyperphosphorylated tau protein--the two foremost histopathological signs of AD--have been implicated in mitochondrial dysfunction. Neurosteroids have recently shown promise in alleviating cognitive and neuronal sequelae of AD. The present study evaluates the impact of neurosteroids belonging to the sex hormone family (progesterone, estradiol, estrone, testosterone, 3α-androstanediol) on mitochondrial dysfunction in cellular models of AD: human neuroblastoma cells (SH-SY5Y) stably transfected with constructs encoding (1) the human amyloid precursor protein (APP) resulting in overexpression of APP and Aβ, (2) wild-type tau (wtTau), and (3) mutant tau (P301L), that induces abnormal tau hyperphosphorylation. We show that while APP and P301L cells both display a drop in ATP levels, they present distinct mitochondrial impairments with regard to their bioenergetic profiles. The P301L cells presented a decreased maximal respiration and spare respiratory capacity, while APP cells exhibited, in addition, a decrease in basal respiration, ATP turnover, and glycolytic reserve. All neurosteroids showed beneficial effects on ATP production and mitochondrial membrane potential in APP/Aβ overexpressing cells while only progesterone and estradiol increased ATP levels in mutant tau cells. Of note, testosterone was more efficient in alleviating Aβ-induced mitochondrial deficits, while progesterone and estrogen were the most effective neurosteroids in our model of AD-related tauopathy. Our findings lend further support to the neuroprotective effects of neurosteroids in AD and may open new avenues for the development of gender-specific therapeutic approaches in AD.

Keywords: Amyloid-β peptide; Bioenergetics; Mitochondria; Neurosteroids; Tau protein.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Characterization of bioenergetic deficits in APP cells. a Oxygen consumption rate (OCR) and b extracellular acidification rate (ECAR) of Mock and APP cells were simultaneously measured using a XF24 Analyzer (Seahorse Bioscience). The sequential injection of mitochondrial inhibitors is indicated by arrows (see details in the “Materials and methods” section). Changes in the OCR and ECAR are shown as a percent change from baseline (=100 %, dashed line). c Values corresponding to the different bioenergetic parameters are represented as mean ± SEM (n = 8–10 replicates). d ATP levels and e mitochondrial membrane potential (MMP) in Mock and APP cells. Values represent the mean ± SEM (n = 12–18 replicates of three independent experiments). Student unpaired t test, *P < 0.05; ***P < 0.001. O oligomycin, F FCCP, R/A rotenone/antimycin A
Fig. 2
Fig. 2
Characterization of bioenergetic deficits in P301L cells. a Oxygen consumption rate (OCR) and b extracellular acidification rate (ECAR) of wtTau and P301L cells were simultaneously measured using a XF24 Analyzer (Seahorse Bioscience). The sequential injection of mitochondrial inhibitors is indicated by arrows (see details in the “Materials and methods” section). Changes in the OCR and ECAR are shown as a percent change from baseline (=100 %, dashed line). c Values corresponding to the different bioenergetic parameters are represented as mean ± SEM (n = 8–10 replicates). d ATP levels and e mitochondrial membrane potential (MMP) in wtTau and P301L cells. Values represent the mean ± SEM (n = 12–18 replicates of three independent experiments). Student unpaired t test, *P < 0.05; ***P < 0.001. O oligomycin, F FCCP, R/A rotenone/antimycin A
Fig. 3
Fig. 3
Neurosteroids increase ATP level and MMP in APP and P301L cells. ATP levels and MMP were measured after neurosteroid treatment for 24 h at a concentration of 100 nM in APP cells (a–b) and P301L cells (c–d), respectively. Values represent the mean ± SEM (n = 12–18 replicates of three independent experiments) and were normalized to 100 % of untreated Mock cells (a–b) or untreated wtTau cells (c–d). The values for untreated APP (a–b) and P301L cells (c–d) were also indicated by a dashed line. One-way ANOVA and post hoc Dunnett’s multiple comparison test versus untreated Mock or wtTau, *P < 0.05; **P < 0.01; ***P < 0.001. P progesterone, E2 estradiol, E1 estrone, T testosterone, 3α 3α-androstanediol
Fig. 4
Fig. 4
Effects of neurosteroids on bioenergetic parameters in APP cells. a Basal respiration, b ATP turnover, c maximal respiration, d spare respiratory capacity, and e glycolytic reserve were measured after neurosteroid treatment for 24 h at a concentration of 100 nM in APP cells, using a XF24 Analyzer (Seahorse Bioscience). Values represent the mean ± SEM (n = 8–10 replicates) and were normalized to 100 % of the control group (untreated APP cells, dashed line). One-way ANOVA and post hoc Dunnett’s multiple comparison test versus control, *P < 0.05; ***P < 0.001. P progesterone, E2 estradiol, E1 estrone, T testosterone, 3α 3α-androstanediol
Fig. 5
Fig. 5
Effects of neurosteroids on bioenergetic parameters in P301L cells. a Basal respiration, b ATP turnover, c maximal respiration, d spare respiratory capacity, and e glycolytic reserve were measured after neurosteroid treatment for 24 h at a concentration of 100 nM in P301L cells, using a XF24 Analyzer (Seahorse Bioscience). Values represent the mean ± SEM (n = 8–10 replicates) and were normalized to 100 % of the control group (untreated P301L cells, dashed line). One-way ANOVA and post hoc Dunnett’s multiple comparison test versus control, *P < 0.05; ***P < 0.001. P progesterone, E2 estradiol, E1 estrone, T testosterone, 3α 3α-androstanediol
Fig. 6
Fig. 6
Neurosteroids differentially regulate the bioenergetic profile in APP/Aβ and abnormal tau-overexpressing cells. a–b Characterization of bioenergetic profiles of APP cells after neurosteroid treatment along two axes. Degree of a ATP turnover or b spare respiratory capacity is shown (in ordinate) in function of glycolytic reserve (in abscissa). The same parameters are displayed for P301L cells (c–d), respectively. Values represent the mean of each group normalized to the control group (untreated APP or P301L cells = 100 %). Significant changes upon respiratory parameters are highlighted by dashed circles. P progesterone, E2 estradiol, E1 estrone, T testosterone, 3α 3α-androstanediol, aero. aerobic, metab. metabolic, glyco. glycolytic
Fig. 7
Fig. 7
Neurosteroids are protective against the H2O2-induced drop of ATP levels in APP and P301L cells. a APP cells and b P301L cells were pre-treated 24 h with progesterone (P), estradiol (E2), and testosterone (T) and then stressed with a 250 μM H2O2 (APP cells) or b 500 μM H2O2 (P301L cells). Values represent the mean ± SEM (n = 12–18 replicates of three independent experiments) and were normalized to 100 % of APP cells (a) and P301L cells (b) not pre-treated with our selection of neurosteroids (Ctr control). One-way ANOVA and post hoc Dunnett’s multiple comparison test versus control APP or P301L, *P < 0.05; **P < 0.01; ***P < 0.001
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