Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer’s Mouse Model

Tian Wang, Jia Yao, Shuhua Chen, Zisu Mao, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Previously, we reported that the neurosteroid allopregnanolone (Allo) promoted neural stem cell regeneration, restored cognitive function, and reduced Alzheimer’s Disease (AD) pathology in the triple transgenic Alzheimer’s mouse model (3xTgAD). To investigate the underlying systems biology of Allo action in AD models in vivo, we assessed the regulation of Allo on the bioenergetic system of the brain. Outcomes of these analysis indicated that Allo significantly reversed deficits in mitochondrial respiration and biogenesis and key mitochondrial enzyme activity and reduced lipid peroxidation in the 3xTgAD mice in vivo. To explore the mechanisms by which Allo regulates the brain metabolism, we conducted targeted transcriptome analysis. These data further confirmed that Allo upregulated genes involved in glucose metabolism, mitochondrial bioenergetics, and signaling pathways while simultaneously downregulating genes involved in Alzheimer’s pathology, fatty acid metabolism, and mitochondrial uncoupling and dynamics. Upstream regulatory pathway analysis predicted that Allo induced peroxisome proliferator-activated receptor gamma (PPARG) and coactivator 1-alpha (PPARGC1A) pathways while simultaneously inhibiting the presenilin 1 (PSEN 1), phosphatase and tensin homolog (PTEN), and tumor necrosis factor (TNF) pathways to reduce AD pathology. Collectively, these data indicate that Allo functions as a systems biology regulator of bioenergetics, cholesterol homeostasis, and β-amyloid reduction in the brain. These systems are critical to neurological health, thus providing a plausible mechanistic rationale for Allo as a therapeutic to promote neural cell function and reduce the burden of AD pathology.

Original languageEnglish (US)
Pages (from-to)178-188
Number of pages11
JournalNeurotherapeutics
Volume17
Issue number1
DOIs
StatePublished - Jan 1 2020

Keywords

  • Allopregnanolone
  • Alzheimer’s disease
  • bioenergetics
  • mitochondria
  • therapeutics
  • transcriptome

ASJC Scopus subject areas

  • Pharmacology
  • Clinical Neurology
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Allopregnanolone Reverses Bioenergetic Deficits in Female Triple Transgenic Alzheimer’s Mouse Model'. Together they form a unique fingerprint.

Cite this