Dataset Information

Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C.

ABSTRACT: Cerebral elevation of 42-residue amyloid ?-peptide (A?42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect A? generation, the role of cholesterol in the pathogenesis of AD is not clear yet. Recently, we have shown that increased membrane cholesterol levels downregulates phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of phospholipase C (PLC). In this study, we tested whether membrane cholesterol levels may affect the A?42 production via changing PIP2 levels. Increasing membrane cholesterol levels decreased PIP2 and increased secreted A?42. Supplying PIP2, by using a PIP2-carrier system, blocked the effect of cholesterol on A?42. We also found that cholesterol increased the expressions of ?1 and ?3 PLC isoforms (PLC?1, PLC?3). Silencing the expression of PLC?1 prevented the effects of cholesterol on PIP2 levels as well as on A?42 production, suggesting that increased membrane cholesterol levels increased secreted A?42 by downregulating PIP2 via enhancing the expression of PLC?1. Thus, cholesterol metabolism may be linked to A?42 levels via PLC?1 expression and subsequent changes in PIP2 metabolism.

SUBMITTER: Chun YS

PROVIDER: S-EPMC4437359 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C.

Chun Yoon Sun YS Oh Hyun Geun HG Park Myoung Kyu MK Kim Tae-Wan TW Chung Sungkwon S

Journal of neurodegenerative diseases 20130307

Cerebral elevation of 42-residue amyloid β-peptide (Aβ42) triggers neuronal dysfunction in Alzheimer's disease (AD). Even though a number of cholesterol modulating agents have been shown to affect Aβ generation, the role of cholesterol in the pathogenesis of AD is not clear yet. Recently, we have shown that increased membrane cholesterol levels downregulates phosphatidylinositol 4,5-bisphosphate (PIP2) via activation of phospholipase C (PLC). In this study, we tested whether membrane cholesterol ...[more]

PMID: 26316988

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Project description:The advancement in site-directed spin labeling of proteins has enabled EPR studies to expand into newer research areas within the umbrella of protein-membrane interactions. Recently, membrane remodeling by amyloidogenic and non-amyloidogenic proteins has gained a substantial interest in relation to driving and controlling vital cellular processes such as endocytosis, exocytosis, shaping of organelles like endoplasmic reticulum, Golgi and mitochondria, intracellular vesicular trafficking, formation of filopedia and multivesicular bodies, mitochondrial fusion and fission, and synaptic vesicle fusion and recycling in neurotransmission. Misregulation in any of these processes due to an aberrant protein (mutation or misfolding) or alteration of lipid metabolism can be detrimental to the cell and cause disease. Dissection of the structural basis of membrane remodeling by proteins is thus quite necessary for an understanding of the underlying mechanisms, but it remains a formidable task due to the difficulties of various common biophysical tools in monitoring the dynamic process of membrane binding and bending by proteins. This is largely since membranes generally complicate protein structure analysis and this problem is amplified for structural analysis in the presence of different types of membrane curvatures. Recent EPR studies on membrane remodeling by proteins show that a significant structural information can be generated to delineate the role of different protein modules, domains and individual amino acids in the generation of membrane curvature. These studies also show how EPR can complement the data obtained by high resolution techniques such as X-ray and NMR. This perspective covers the application of EPR in recent studies for understanding membrane remodeling by amyloidogenic and non-amyloidogenic proteins that is useful for researchers interested in using or complimenting EPR to gain better understanding of membrane remodeling. We also discuss how a single protein can generate different type of membrane curvatures using specific conformations for specific membrane structures and how EPR is a versatile tool well-suited to analyze subtle alterations in structures under such modifying conditions which otherwise would have been difficult using other biophysical tools.

Dataset Information

Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C.

Publications

Increasing Membrane Cholesterol Level Increases the Amyloidogenic Peptide by Enhancing the Expression of Phospholipase C.

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