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Potential Use of the Cholesterol Transfer Inhibitor U18666A as a Potent Research Tool for the Study of Cholesterol Mechanisms in Neurodegenerative Disorders

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Abstract

Cholesterol is an essential component of mammalian cell membranes and a precursor for crucial signaling molecules. The brain contains the highest level of cholesterol in the body, and abnormal cholesterol metabolism links to many neurodegenerative disorders. The results indicate that faulty cholesterol metabolism is a common feature among people living with neurodegenerative conditions. The researchers suggest that restoring cholesterol levels may become a beneficial new strategy in treating certain neurodegenerative conditions. Several neurodegenerative disorders, such as Alzheimer’s disease (AD), Niemann-Pick type C (NPC) disease, and Parkinson’s disease (PD), have been connected to abnormalities in brain cholesterol metabolism. Consequently, using a lipid research tool is vital to study further and understand the effect of lipids in neurodegenerative disorders such as NPC, AD, PD, and Huntington’s disease (HD). U18666A, also known as 3-(2-(diethylamino) ethoxy) androst-5-en-17-one, is a pharmaceutical drug that suppresses cholesterol trafficking and is a well-known class-2 amphiphile. U18666A has performed many functions, allowing for essential discoveries in lipid studies and shedding light on the pathophysiology of neurodegenerative disorders. Additionally, U18666A prevented the downregulation of low-density lipoprotein (LDL) receptors that are induced by LDL and led to the buildup of cholesterol in lysosomes. Numerous studies show that U18666A impacts the function of cholesterol trafficking to control the metabolism and transport of amyloid precursor proteins (APPs). Treating cortical neurons with U18666A may provide a new in vitro model system for studying the underlying molecular process of NPC, AD, HD, and PD. In this article, we review the mechanism and function of U18666A as a vital tool for studying cholesterol mechanisms in neurological diseases related to abnormal cholesterol metabolism, such as AD, NPC, HD, and PD.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

PD :

Parkinson’s disease

SLOS :

Smith-Lemli Opitz syndrome

NPC :

Niemann-Pick type C disease

HD :

Huntington’s disease

AD :

Alzheimer’s disease

DHEA :

Dehydroepiandrosterone

SSD :

Sterol-sensing domain

CNS :

Central nervous system

Aβ :

Amyloid β

BBB :

Blood-brain barrier

VLDLR :

Very low-density lipoprotein receptor

LRP :

LDLR-related protein

ER :

Endoplasmic reticulum

UC :

Unesterified cholesterol

EC :

Esterified cholesterol

NTD :

N-terminal domain (NTD)

SSD :

Sterol-sensing domain

IRS :

Insulin receptor substrate

NSE :

Neuron-specific enolase

MS :

Multiple sclerosis

ALS :

Amyotrophic lateral sclerosis

TC :

Total cholesterol

APPs :

Amyloid precursor proteins

EL :

Endosomal-lysosomal

PNS :

Peripheral nervous system

Cdk5 :

Cyclin-dependent kinase 5

DOTAP :

1,2-Dioleoyl-3-trimethylammoniumpropane

DOPE :

Dioleoylphosphatidylethanolamine

DOPC :

Dioleoyl-phosphocholine

LMP :

Lysosomal membrane permeabilization

SDS :

Sodium dodecyl sulfate

MPP + :

1-Methyl-4-phenylpyridinium

SREBP :

Sterol regulatory element-binding protein

LXRs :

Liver X receptors

ABCA1 :

ATP-binding cassette transporter A1

HMG-CoA :

3-Hydroxy-3-methyl-glutaryl coenzyme A

NFT :

Neurofibrillary tangles

FDA :

Food and Drug Administration

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Authors and Affiliations

  1. Viro & Biotech, Tehran, Iran

    Saman Yasamineh & Omid Gholizadeh

  2. Department of Nanobiotechnology, Tehran, Iran

    Fatemeh Jabbari Mehrabani

  3. Windsor University School of Medicine, Cayon, Saint Kitts and Nevis

    Ehsan Derafsh

  4. Biology, Molecular Research Center, Biology, Santiago, Chile

    Renizo Danihiel Cosimi

  5. Biomedical Engineering Department, Shahed University, Tehran, Iran

    Amir Mohammad Karimi Forood

  6. Department of Forensic Medicine, School of Medicine, Iran University of Medical Sciences, Tehran, Iran

    Siamak Soltani

  7. Department Of Microbiology, Faculty of Basic Sciences, Tehran Central Branch, Islamic Azad University, Tehran, Iran

    Meead Hadi

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Contributions

S.Y.: validation, investigation, writing original draft–review and editing, resources, visualization, software, formal analysis, conceptualization. M.H.: writing-review and editing, investigation. F.J.M., E.D., R.D.C.P., A.M.K.F., and S.S.: writing-review and editing, investigation. O.G.: corresponding author, writing original draft-review and editing. All authors read and approved the final manuscript.

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Yasamineh, S., Mehrabani, F.J., Derafsh, E. et al. Potential Use of the Cholesterol Transfer Inhibitor U18666A as a Potent Research Tool for the Study of Cholesterol Mechanisms in Neurodegenerative Disorders. Mol Neurobiol (2023). https://doi.org/10.1007/s12035-023-03798-7

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