title: Tissue transglutaminase colocalizes with extracellular matrix proteins in cerebral amyloid angiopathy.
abstract: Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aβ) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aβ in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aβ deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aβ. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aβ in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aβ aggregation to cross-linking of ECM proteins resulting in ECM restructuring.
authors.affiliation: Department of Anatomy and Neurosciences, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands. am.dejager@vumc.nl
authors.forename: Mieke
authors.initials: M
authors.lastname: de Jager
authors.forename: Berend
authors.initials: B
authors.lastname: van der Wildt
authors.forename: Emma
authors.initials: E
authors.lastname: Schul
authors.forename: John G J M
authors.initials: JG
authors.lastname: Bol
authors.forename: Sjoerd G
authors.initials: SG
authors.lastname: van Duinen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drukarch
authors.forename: Micha M M
authors.initials: MM
authors.lastname: Wilhelmus
mesh_terms: D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D028226:Amyloidosis, Familial / Q000378:metabolism*; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism*; D028243:Cerebral Amyloid Angiopathy, Familial; D002536:Cerebral Arteries / Q000378:metabolism*; D002543:Cerebral Hemorrhage / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D014018:Tissue Distribution; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins