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Neurotherapeutics

, Volume 16, Issue 3, pp 710–724 | Cite as

CYP46A1 Activation by Efavirenz Leads to Behavioral Improvement without Significant Changes in Amyloid Plaque Load in the Brain of 5XFAD Mice

  • Alexey M. Petrov
  • Morrie Lam
  • Natalia Mast
  • Jean Moon
  • Yong Li
  • Erin Maxfield
  • Irina A. PikulevaEmail author
Original Article
  • 372 Downloads

Abstract

Efavirenz, the FDA-approved anti-retroviral medication, is evaluated in the clinical trial in patients with mild cognitive impairment or early dementia due to Alzheimer’s disease. Efavirenz is assessed for activation of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme that converts cholesterol to 24-hydroxycholesterol. Cholesterol 24-hydroxylation is the major pathway for brain cholesterol removal, and a mechanism that controls brain cholesterol turnover. The present study tested efavirenz on 5XFAD mice (an Alzheimer’s model) at a very low daily dose of 0.1 mg/kg body weight. Efavirenz treatment started from three months of age, after amyloid plague appearance, and continued for 6 months. This treatment led to CYP46A1 activation in the brain, enhancement of brain cholesterol turnover, behavioral improvements, reduction in microglia activation but increased astrocyte reactivity. The levels of the soluble and insoluble amyloid 40 and 42 peptides were unchanged while the number and area of the dense core amyloid plaques were slightly decreased. The measurements of the brain levels of several pre- and post-synaptic proteins (Munc13-1, PSD-95, gephyrin, synaptophysin, synapsin-1, and calbindin-D28k) suggested efavirenz effect at the synaptic level. Efavirenz treatment in the present work seems to represent a model of behavioral and other improvements independent of the levels of the amyloid peptides and provides insight into potential outcomes of the future clinical trial.

Key Words

CYP46A1 Efavirenz Alzheimer’s disease 24-hydroxycholesterol Astrocytes Microglia Synaptic proteins 

Abbreviations

Amyloid β Peptide

AD

Alzheimer’s Disease

APP

Amyloid Precursor Protein

CS

Conditioned Stimulus

CYP46A1

Cytochrome P450 46A1

EFV

Efavirenz

GABA

Gamma-Aminobutyric Acid

GFAP

Glial Fibrillary Acidic Protein

24HC

24-Hydroxycholesterol

HMGCR

3-Hydroxy-3-Methylglutaryl-CoA Reductase

Iba1

Ionized Calcium Binding Adaptor Molecule 1

LXR

Liver X Receptor

MWM

Morris Water Maze

NMDAR

N-Methyl-D-Aspartate Receptors

PBS

Phosphate Buffer Saline

US

Unconditioned Stimulus

Notes

Acknowledgments

This work was supported in part in by National Institute of General Medical Sciences grant GM062882 (IAP). The authors thank the Visual Sciences Research Center Core Facilities (supported by National Institutes of Health Grant P30 EY11373) for assistance with mouse breeding (Heather Butler and Kathryn Franke), animal genotyping (John Denker), tissue sectioning (Catherine Doller), and microscopy (Anthony Gardella). We are also grateful to Dr. Hiroyuki Arakawa for behavioral testing.

Author Contributions

IAP conceived and designed the study; ML, NM, JM, YL, and EM performed the experiments; IP, NM, AMP, and ML analyzed the data; IAP and AMP wrote the paper; IAP acquired funding.

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.

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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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