title: Zinc affects the proteolytic stability of Apolipoprotein E in an isoform-dependent way.
abstract: The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset/progression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma samples from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria 3010, Australia.
authors.forename: He
authors.initials: H
authors.lastname: Xu
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027 WA, Australia.
authors.forename: Veer B
authors.initials: VB
authors.lastname: Gupta
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027 WA, Australia.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Martins
authors.affiliation: Centre of Excellence for Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, 6027 WA, Australia.
authors.forename: Ralph N
authors.initials: RN
authors.lastname: Martins
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria 3010, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Fowler
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria 3010, Australia.
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria 3010, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria 3010, Australia. Electronic address: paul.adlard@florey.edu.au.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D010949:Plasma / Q000187:drug effects*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D057057:Serine Proteases / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D014131:Trace Elements / Q000378:metabolism / Q000494:pharmacology*; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D020033:Protein Isoforms; D014131:Trace Elements; D004492:Edetic Acid; D057057:Serine Proteases; D013917:Thrombin; D015032:Zinc
keywords: Apolipoprotein E; Proteolytic stability; Zinc