Dataset Information

Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of ?-amyloid precursor protein.

ABSTRACT: Familial Alzheimer's disease (FAD)-associated presenilin 1 (PS1) serves as a catalytic subunit of ?-secretase complex, which mediates the proteolytic liberation of ?-amyloid (A?) from ?-amyloid precursor protein (APP). In addition to its proteolytic role, PS1 is involved in non-proteolytic functions such as protein trafficking and ion channel regulation. Furthermore, postmortem AD brains as well as AD patients showed dysregulation of cholesterol metabolism. Since cholesterol has been implicated in regulating A? production, we investigated whether the FAD PS1-associated cholesterol elevation could influence APP processing. We found that in CHO cells stably expressing FAD-associated PS1 ?E9, total cholesterol levels are elevated compared to cells expressing wild-type PS1. We also found that localization of APP in cholesterol-enriched lipid rafts is substantially increased in the mutant cells. Reducing the cholesterol levels by either methyl-?-cyclodextrin or an inhibitor of CYP51, an enzyme mediating the elevated cholesterol in PS1 ?E9-expressing cells, significantly reduced lipid raft-associated APP. In contrast, exogenous cholesterol increased lipid raft-associated APP. These data suggest that in the FAD PS1 ?E9 cells, the elevated cellular cholesterol level contributes to the altered APP processing by increasing APP localized in lipid rafts.

SUBMITTER: Cho YY

PROVIDER: S-EPMC6347419 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of β-amyloid precursor protein.

Cho Yoon Young YY Kwon Oh-Hoon OH Park Myoung Kyu MK Kim Tae-Wan TW Chung Sungkwon S

PloS one 20190125 1

Familial Alzheimer's disease (FAD)-associated presenilin 1 (PS1) serves as a catalytic subunit of γ-secretase complex, which mediates the proteolytic liberation of β-amyloid (Aβ) from β-amyloid precursor protein (APP). In addition to its proteolytic role, PS1 is involved in non-proteolytic functions such as protein trafficking and ion channel regulation. Furthermore, postmortem AD brains as well as AD patients showed dysregulation of cholesterol metabolism. Since cholesterol has been implicated ...[more]

PMID: 30682043

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Project description:Elevated levels of cellular cholesterol have been identified as one factor contributing to the onset of Alzheimer's disease (AD). Specific interaction between cholesterol and the amyloid precursor protein (APP), investigated via NMR experiments and computational studies, has been proposed to play a critical role in the processing of APP by secretases and the biogenesis of amyloid-β (Aβ) protein. We present all-atom molecular dynamics simulations of the 40-residue congener of the C-terminal domain of APP, C9916-55 (C99), in cholesterol-enriched DMPC lipid bilayers. We investigated the effect of cholesterol concentration on the conformational ensemble of wild-type C99 and C99-cholesterol associations at the low pH of endosomal environments, at which residues E22 and D23 are neutral. C99 was also characterized in liquid ordered domains for Dutch (E22Q) and Iowa (D23N) Familial AD mutants at low pH and for the wild-type sequence using protonation states characteristic of neutral pH. Our results reproduce the equilibrium constant of past NMR characterizations of the C99-cholesterol interaction but are not consistent with the C99-cholesterol binding hypothesis. We find that the lifetimes of both DMPC and cholesterol complexed with C99 display a power-law distribution of residence lifetimes. Longer-lived C99-DMPC and C99-cholesterol complexes are primarily stabilized by salt bridges and hydrogen bonds of lysine amines to phosphate and hydroxyl groups. Nevertheless, specific interfaces for C99-cholesterol association which are not present for DMPC can be identified. Changes to C99-cholesterol interfaces are found to depend on C99 tilt angle and orientation of the juxtamembrane domain of C99 containing residues E22 and D23. These observations support a more nuanced view of the C99-cholesterol interaction than has previously been suggested. We propose that cholesterol modulates the conformation and activity of C99 and other small transmembrane proteins indirectly through induction of the liquid ordered phase and directly through hydrogen bonding. This suggests a critical role for membrane heterogeneity introduced by cholesterol in modulating the structural ensemble of C99 and the production of Aβ.

Project description:Increasing evidence has shown a correlation between chronic periodontitis (CP) and Alzheimer's disease (AD). Nevertheless, there is still a lack of direct evidence, and especially key molecules to connect the two diseases. This study aims to investigate potential protein links between CP and AD within the inflammatory aspect. The hippocampus of CP model mice and controls were collected, and changes in protein expression were evaluated using two-dimensional differential in-gel electrophoresis (2D-DIGE) analysis combined with liquid chromatography tandem mass spectrometry. A total of 15 differentially expressed proteins were identified in CP model mice, as compared with the controls. Among them, S100-A9, transthyretin, Cofilin 2, peroxiredoxin 2, and lipocalin-2 were validated by Western blot according to their dual function both in inflammation and AD. Based on 2D-DIGE analysis, CP animal model had higher levels of S100-A9, Cofilin 2, peroxiredoxin 2, and lipocalin-2 compared to controls. The level of Cofilin 2, one of the well-established proteins in the pathology of AD, was strongly correlated with the time course of CP pathology, indicating a specific molecular correlation between CP and AD. Moreover, the in vivo results showed the level of Cofilin 2 increased significantly along with a prominent increase of the phosphorylation of protein phosphatase 2 (PP2A) and tau protein in the cell lysates of Porphyromonas gingivalis (P.g-LPS)-treated SK-N-SH APPwt cells. Cofilin 2 inhibition resulted in a sharp decrease in PP2A dependent of tau phosphorylation. Furthermore, tumor growth factor (TGF)-β1 was one of the most important inflammatory cytokines for the Pg-LPS-induced Cofilin 2 upregulation in SK-N-SH APPwt cells. These results showed inflammation served as the bond between CP and AD, whereas inflammatory related proteins could be the key linkers between the two diseases. Determining the association between CP and AD at the molecular mechanism will not only hold the direct evidence of the association between the two diseases but also provide a new way of preventing and treating AD: the effective prevention and treatment of CP could serve as a useful method to alleviate the development of AD.

Dataset Information

Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of ?-amyloid precursor protein.

Publications

Elevated cellular cholesterol in Familial Alzheimer's presenilin 1 mutation is associated with lipid raft localization of β-amyloid precursor protein.

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