Opposite Roles of Cholesterol and Lanosterol in Lipid Membrane on Amyloid-Beta 42 Peptide Nucleation and Fibril Formation.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2024-12-21 DOI:10.1021/acschemneuro.4c00707
Kyohei Akiho, Akane Iida-Adachi, Hideki Nabika
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引用次数: 0

Abstract

Molecular self-assembly of amyloid-beta peptides to form fibrillar aggregates is a known cause of Alzheimer's disease. Although homogeneous nucleation of amyloid-beta is unfavorable, heterogeneous nucleation of amyloid-beta in cell membranes plays a key role in fibril formation. We observed these opposite roles in the effects of cholesterol and lanosterol, the precursor of cholesterol in the brain, on nucleation. As previously reported, cholesterol accelerated nucleation, whereas lanosterol decelerated it when mixed with dioleoyl-phosphatidylcholine at 20%. The observed opposite effects of cholesterol and lanosterol on nucleation do not correlate with the differences in the mechanical and thermodynamic nature of mixed membranes. However, the affinity of amyloid-beta to the inner membrane seems to be related to the opposite effects on nucleation kinetics. Cholesterol reduced the insertion of amyloid-beta into the lipid membrane, whereas lanosterol promoted the insertion of amyloid-beta into the membrane, which would make amyloid-beta more tightly bound by lipid molecules and reduce its diffusivity in the membrane and consequently inhibit nucleation. Our study provides insights into the effects of sterol compounds other than the well-investigated cholesterol on the self-assembly of amyloid-beta to clarify the molecular basis underlying Alzheimer's disease pathology and to develop targeted therapeutic strategies.

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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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