Alzheimer Disease: Cheng H

Cheng H, Vetrivel KS, Gong P, Meckler X, Parent A, Thinakaran G. · University of Chicago, IL, USA. · Nat Clin Pract Neurol. · Pubmed #17611486 No free full text.

Abstract: Alzheimer's disease (AD) is the most common cause of age-related dementia. Pathologically, AD is characterized by the deposition in the brain of amyloid-beta peptides derived from proteolysis of amyloid precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. A growing body of evidence implicates cholesterol and cholesterol-rich membrane microdomains in amyloidogenic processing of APP. Here, we review recent findings regarding the association of BACE1, gamma-secretase and APP in lipid rafts, and discuss potential therapeutic strategies for AD that are based on knowledge gleaned from the membrane environment that fosters APP processing.

Cheng H, Vetrivel KS, Drisdel RC, Meckler X, Gong P, Leem JY, Li T, Carter M, Chen Y, Nguyen P, Iwatsubo T, Tomita T, Wong PC, Green WN, Kounnas MZ, Thinakaran G. · Department of Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA. · J Biol Chem. · Pubmed #19028695 No free full text.

Abstract: Proteolytic processing of amyloid precursor protein (APP) by beta- and gamma-secretases generates beta-amyloid (Abeta) peptides, which accumulate in the brains of individuals affected by Alzheimer disease. Detergent-resistant membrane microdomains (DRM) rich in cholesterol and sphingolipid, termed lipid rafts, have been implicated in Abeta production. Previously, we and others reported that the four integral subunits of the gamma-secretase associate with DRM. In this study we investigated the mechanisms underlying DRM association of gamma-secretase subunits. We report that in cultured cells and in brain the gamma-secretase subunits nicastrin and APH-1 undergo S-palmitoylation, the post-translational covalent attachment of the long chain fatty acid palmitate common in lipid raft-associated proteins. By mutagenesis we show that nicastrin is S-palmitoylated at Cys(689), and APH-1 is S-palmitoylated at Cys(182) and Cys(245). S-Palmitoylation-defective nicastrin and APH-1 form stable gamma-secretase complexes when expressed in knock-out fibroblasts lacking wild type subunits, suggesting that S-palmitoylation is not essential for gamma-secretase assembly. Nevertheless, fractionation studies show that S-palmitoylation contributes to DRM association of nicastrin and APH-1. Moreover, pulse-chase analyses reveal that S-palmitoylation is important for nascent polypeptide stability of both proteins. Co-expression of S-palmitoylation-deficient nicastrin and APH-1 in cultured cells neither affects Abeta40, Abeta42, and AICD production, nor intramembrane processing of Notch and N-cadherin. Our findings suggest that S-palmitoylation plays a role in stability and raft localization of nicastrin and APH-1, but does not directly modulate gamma-secretase processing of APP and other substrates.

Vetrivel KS, Zhang X, Meckler X, Cheng H, Lee S, Gong P, Lopes KO, Chen Y, Iwata N, Yin KJ, Lee JM, Parent AT, Saido TC, Li YM, Sisodia SS, Thinakaran G. · Department of Neurobiology and Neurology, The University of Chicago, Chicago, Illinois 60637, USA. · J Biol Chem. · Pubmed #18456655 links to  free full text

Abstract: Cerebral deposition of beta-amyloid (Abeta) peptides is a pathological hallmark of Alzheimer disease. Intramembranous proteolysis of amyloid precursor protein by a multiprotein gamma-secretase complex generates Abeta. Previously, it was reported that CD147, a glycoprotein that stimulates production of matrix metalloproteinases (MMPs), is a subunit of gamma-secretase and that the levels of secreted Abeta inversely correlate with CD147 expression. Here, we show that the levels and localization of CD147 in fibroblasts, as well as postnatal expression and distribution in brain, are distinct from those of integral gamma-secretase subunits. Notably, we show that although depletion of CD147 increased extracellular Abeta levels in intact cells, membranes isolated from CD147-depleted cells failed to elevate Abeta production in an in vitro gamma-secretase assay. Consistent with an extracellular source that modulates Abeta metabolism, synthetic Abeta was degraded more rapidly in the conditioned medium of cells overexpressing CD147. Moreover, modulation of CD147 expression had no effect on epsilon-site cleavage of amyloid precursor protein and Notch1 receptor. Collectively, our results demonstrate that CD147 modulates Abeta levels not by regulating gamma-secretase activity, but by stimulating extracellular degradation of Abeta. In view of the known function of CD147 in MMP production, we postulate that CD147 expression influences Abeta levels by an indirect mechanism involving MMPs that can degrade extracellular Abeta.

Cheng H, Xu J, McKeel DW, Han X. · Division of Bioorganic Chemistry and Molecular Pharmacology, Department of Internal Medicine, Washington University School of Medicine, Box 8020, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. · Cell Mol Biol (Noisy-le-grand). · Pubmed #14528918 No free full text.

Abstract: Recently, we have demonstrated that sulfatide content was substantially depleted in post-mortem brain samples from subjects with very mild Alzheimer's disease (AD) relative to age-matched controls. However, it is unknown if the observed sulfatide deficiency is AD-specific and what mechanism(s) lead to this depletion. By exploiting the advantages of electrospray ionization mass spectrometry techniques, we examined the specificity and a potential mechanism of sulfatide deficiency in AD in the study. In contrast to the sulfatide depletion observed in AD, it was found that the sulfatide content in post-mortem brain samples from subjects with Parkinson's disease and dementia with Lewy bodies was either higher than or comparable to that observed from controls, respectively, suggesting that sulfatide deficiency is likely specific to AD. Examination of lipid alterations in cultured embryonic rat brain oligodendrocytes treated with amyloid-beta peptide demonstrated that there was no alteration in sulfatide content up to a 24-hr interval after amyloid-beta addition/treatment. However, there were significant decreases in plasmenylethanolamine and increases in sphingomyelin content in the same study. These findings suggest that sulfatide deficiency in AD is unlikely mediated directly by amyloid-beta peptide accumulation. Thus, these results illustrate the specificity of sulfatide deficiency in AD and exclude amyloid-beta accumulation as a factor directly contributing to sulfatide deficiency in AD.

Han X, Fagan AM, Cheng H, Morris JC, Xiong C, Holtzman DM. · Division of Bioorganic Chemistry and Molecular Pharmacology, and the Departments of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. · Ann Neurol. · Pubmed #12838527 No free full text.

Abstract: We recently noted a profound decline in brain sulfatides (ST) in subjects who died with incipient dementia due to Alzheimer's disease. Herein, we measured ST levels in cerebrospinal fluid in cognitively normal elderly and in subjects with mild cognitive impairment due to incipient demenia of the Alzheimer type. There was a significant decrease in cerebrospinal fluid ST and in the ST to phosphatidylinositol ratio in MCI subjects. The ST to phosphatidylinositol ratio accurately differentiated very mildly impaired subjects from controls on an individual basis. The cerebrospinal fluid ST to phosphatidylinositol ratio may be a very useful biomarker for the earliest clinical stage of Alzheimer's disease.

Cheng H. · No affiliation provided · J Am Med Dir Assoc. · Pubmed #16286074 No free full text.

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