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Neurotherapeutics

, Volume 16, Issue 3, pp 635–648 | Cite as

Cholesterol 24-Hydroxylation by CYP46A1: Benefits of Modulation for Brain Diseases

  • Alexey M. Petrov
  • Irina A. PikulevaEmail author
Review

Abstract

Cholesterol 24-hydroxylation is the major mechanism for cholesterol removal from the brain and the reaction catalyzed by cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. This review describes CYP46A1 in the context of cholesterol homeostasis in the brain and summarizes available experimental data on CYP46A1 association with different neurologic diseases, including the mechanisms by which changes in the CYP46A1 activity in the brain could be beneficial for these diseases. The modulation of CYP46A1 activity by genetic and pharmacologic means is also presented along with a brief synopsis of the two clinical trials that evaluate CYP46A1 as a therapeutic target for Alzheimer’s disease as well as Dravet and Lennox–Gastaut syndromes.

Key Words

CYP46A1 Cholesterol 24-Hydroxycholesterol Cholesterol turnover Efavirenz Neurodegeneration 

Abbreviations

24HC

24-Hydroxycholesterol

ACAT1

Acyl-coenzyme A:cholesterol acyltransferase 1

AD

Alzheimer’s disease

APOA1

Apolipoprotein A1

CSF

Cerebrospinal fluid

DHCR7

7-Dehydrocholesterol reductase

DHCR24

∆24-Dehydrocholesterol reductase

HD

Huntington’s disease

LCAT

Lecithin:cholesterol acyltransferase

LXRs

Liver X receptors

MWM

Morris water maze

NMDARs

N-Methyl-d-aspartate receptors

NPC1

Niemann-Pick C1 protein

NPC2

Niemann-Pick C2 protein

PD

Parkinson’s disease

SOAT

Sterol O-acyltransferase

Notes

Acknowledgments

We thank Dr. Natalia Mast for help with the figure preparation. Some of the studies described in this review were supported in part by the National Institute of General Medical Sciences Grant GM062882 and the Alzheimer’s Drug Discovery Foundation Grant 20160601 (Irina A. Pikuleva).

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Supplementary material

13311_2019_731_MOESM1_ESM.pdf (498 kb)
ESM 1 (PDF 498 kb)

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Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Department of Ophthalmology and Visual SciencesCase Western Reserve UniversityClevelandUSA

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