title: Tissue transglutaminase-catalysed cross-linking induces Apolipoprotein E multimers inhibiting Apolipoprotein E's protective effects towards amyloid-beta-induced toxicity.
abstract: Cerebral amyloid angiopathy (CAA) is a pathological hallmark of Alzheimer's disease (AD) and characterized by deposition of amyloid-β (Aβ) protein and smooth muscle cell (SMC) death in cerebral vessel walls. Apolipoprotein E (ApoE) is of importance in both Aβ accumulation and Aβ-mediated toxicity towards SMCs in the cerebral vessel wall, although its exact role in CAA pathogenesis remains unclear. Tissue transglutaminase (tTG) is an enzyme capable of inducing both protein complexes and altered protein bioactivity via post-translational cross-linking. In CAA, tTG and its catalytic activity are associated with deposited Aβ. Furthermore, several apolipoproteins are known substrates of tTG. We therefore investigated whether ApoE is a substrate for tTG and if this affects ApoE's bioactivity. We found strong binding of different ApoE isoforms with tTG and demonstrated tTG-catalysed ApoE multimers. In post-mortem human AD cases, ApoE colocalized with in situ active tTG in CAA. Moreover, human brain SMCs treated with Aβ demonstrated enhanced secretion of both ApoE and tTG, and of TG cross-links in the extracellular matrix. Interestingly, tTG-catalysed cross-linked ApoE failed to protect SMCs against Aβ-mediated cytotoxicity. Together, our data demonstrate a novel tTG-driven post-translational modification of ApoE that might play an important role in CAA. Cerebral amyloid angiopathy (CAA) is a pathological hallmark of Alzheimer's disease (AD) and characterized by amyloid-β (Aβ) protein deposition and cerebral smooth muscle cell (SMC) death. We found that, in contrast to normal vessels, in CAA apolipoprotein E (ApoE) is cross-linked by tissue transglutaminase (tTG) resulting in stable ApoE complexes. These complexes no longer protect cerebral SMC from Aβ-mediated toxicity. Our findings demonstrate a novel mechanism explaining the Aβ-mediated cerebral SMC cell death characteristic of CAA in AD cases.
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: de Jager
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drukarch
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Hofstee
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: John
authors.initials: J
authors.lastname: Brevé
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Cornelis A M
authors.initials: CA
authors.lastname: Jongenelen
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: John G J M
authors.initials: JG
authors.lastname: Bol
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Micha M M
authors.initials: MM
authors.lastname: Wilhelmus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism*; D015153:Blotting, Western; D002470:Cell Survival; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D005260:Female; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D020033:Protein Isoforms / Q000378:metabolism; D020349:Surface Plasmon Resonance; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D020033:Protein Isoforms; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins
keywords: Alzheimer's disease; apolipoprotein E; cerebral amyloid angiopathy; cross-linking; tissue transglutaminase