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

Grimm, Amandine, Biliouris, Emily E., Lang, Undine E., Gotz, Jurgen, Mensah-Nyagan, Ayikoe Guy and Eckert, Anne (2015) Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein. Cellular and Molecular Life Sciences, 73 1: 201-215. doi:10.1007/s00018-015-1988-x


Author Grimm, Amandine
Biliouris, Emily E.
Lang, Undine E.
Gotz, Jurgen
Mensah-Nyagan, Ayikoe Guy
Eckert, Anne
Title Sex hormone-related neurosteroids differentially rescue bioenergetic deficits induced by amyloid-β or hyperphosphorylated tau protein
Journal name Cellular and Molecular Life Sciences   Check publisher's open access policy
ISSN 1420-9071
1420-682X
Publication date 2015-07-22
Sub-type Article (original research)
DOI 10.1007/s00018-015-1988-x
Open Access Status DOI
Volume 73
Issue 1
Start page 201
End page 215
Total pages 15
Place of publication Basel, Switzerland
Publisher Springer Basel AG
Collection year 2016
Language eng
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.
Keyword Amyloid-β peptide
Bioenergetics
Mitochondria
Neurosteroids
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Queensland Brain Institute Publications
Official 2016 Collection
 
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