Effects of CYP46A1 Inhibition on Long-Term-Depression in Hippocampal Slices ex vivo and 24S-Hydroxycholesterol Levels in Mice in vivo

Frontiers in Molecular Neuroscience
Michael PopiolekSteven Mennerick

Abstract

The manipulation of cholesterol and its metabolites has been hypothesized to be therapeutically beneficial for mood disorders, neurodegenerative disorders, and epilepsies. A major regulator of cholesterol clearance and turnover in the central nervous system is CYP46A1, a brain enriched enzyme responsible for metabolism of cholesterol into 24S-hydroxycholesterol. Inhibition of this enzyme may negatively modulate NMDARs as 24S-hydroxycholesterol was shown to enhance NMDAR function. In addition, alterations of local cholesterol or other changes mediated by CYP46A1 activity could have important influences on central nervous system function. Here we demonstrate that humans and mice display brain region specific and similar CYP46A1 and 24S-hydroxycholesterol distribution. Treatment with distinct classes of CYP46A1 inhibitors led to central 24S-hydroxycholesterol reduction in vivo and ablation of long term depression in hippocampal slices. Our results suggest that rodents show similarity to humans for studying the impact of CYP46A1 inhibitors and that rapid, local modulation of oxysterols can be achieved through CYP46A1 inhibition.

References

Apr 11, 2003·The Journal of Biological Chemistry·Erik G LundDavid W Russell
Dec 4, 2003·Brain Research. Developmental Brain Research·Gang QuanStephen D Turley
Jul 6, 2004·Archives of Biochemistry and Biophysics·Natalia MastIrina A Pikuleva
Feb 5, 2008·The Journal of Comparative Neurology·Denise M O RamirezDavid W Russell
Jun 6, 2009·Annual Review of Biochemistry·David W RussellTiina Kotti
Dec 17, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Kazuhiro TokudaCharles F Zorumski
Oct 14, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Yukitoshi Izumi, Charles F Zorumski
Feb 22, 2012·The EMBO Journal·Alejandro O SoderoCarlos G Dotti
May 30, 2013·Nature Genetics·UNKNOWN GTEx Consortium
Nov 1, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Steven M PaulCharles F Zorumski
Dec 5, 2013·Biochemical and Biophysical Research Communications·Chiara GabbiJan-Åke Gustafsson
Feb 5, 2014·Biochemical and Biophysical Research Communications·Anna MeljonWilliam J Griffiths
Jan 13, 2015·Expert Opinion on Therapeutic Patents·Ahmed KamalShaheer Malik Mohammed
Jan 30, 2015·The Neuroscientist : a Review Journal Bringing Neurobiology, Neurology and Psychiatry·Min-Yu SunSteve Mennerick
Jul 5, 2015·Brain : a Journal of Neurology·Fathia DjeltiNathalie Cartier
Jan 9, 2016·Journal of Neurophysiology·Min-Yu SunSteven Mennerick
Feb 4, 2016·Human Gene Therapy·Sandro AlvesNathalie Cartier
Jul 27, 2017·Frontiers in Molecular Neuroscience·Sophie AyciriexNathalie Cartier
Apr 20, 2019·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Alexey M Petrov, Irina A Pikuleva
Jul 10, 2019·Brain : a Journal of Neurology·Radhia KacherSandrine Betuing
Mar 7, 2020·Proceedings of the National Academy of Sciences of the United States of America·Eylan YutucWilliam J Griffiths
Mar 15, 2020·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Fuxin LuXiangning Jiang

❮ Previous
Next ❯

Citations

Jul 27, 2021·Frontiers in Aging Neuroscience·Irina A Pikuleva, Nathalie Cartier

❮ Previous
Next ❯

Methods Mentioned

BETA
protein assay
electrophoresis
Assay
RNA-seq

Software Mentioned

SigmaStat
EMBOSS Needle
ImageJ
PClamp
GTEx

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.