title: Small heat shock proteins induce a cerebral inflammatory reaction.
abstract: More than 80% of Alzheimer's disease (AD) patients have some degree of cerebral amyloid angiopathy (CAA). In addition to arteries and veins, capillaries can also be affected. Capillary CAA (capCAA), rather than CAA in larger vessels, is associated with flame-like amyloid-beta (Aβ) deposits that may extend beyond the vessel wall and radiate into the neuropil, a phenomenon also known as "dyshoric angiopathy." Aβ deposits in AD, parenchymal as well as (cap)CAA and dyshoric angiopathy, are associated with a local inflammatory reaction, including activation of microglial cells and astrocytes that, among others, produce cytokines and reactive oxygen species. This neuroinflammatory reaction may account for at least part of the cognitive decline. In previous studies we observed that small heat shock proteins (sHsps) are associated with Aβ deposits in AD. In this study the molecular chaperones Hsp20, HspB8 and HspB2B3 were found to colocalize with CAA and capCAA in AD brains. In addition, Hsp20, HspB8 and HspB2B3 colocalized with intercellular adhesion molecule 1 (ICAM-1) in capCAA-associated dyshoric angiopathy. Furthermore, we demonstrated that Hsp20, HspB8 and HspB2B3 induced production of interleukin 8, soluble ICAM-1 and monocyte chemoattractant protein 1 by human leptomeningeal smooth muscle cells and human brain astrocytes in vitro and that Hsp27 inhibited production of transforming growth factor beta 1 and CD40 ligand. Our results suggest a central role for sHsps in the neuroinflammatory reaction in AD and CAA and thus in contributing to cognitive decline.
authors.affiliation: Departments of Neurology and Alzheimer Centre, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. i.bruinsma@neuro.umcn.nl
authors.forename: Ilona B
authors.initials: IB
authors.lastname: Bruinsma
authors.forename: Mieke
authors.initials: M
authors.lastname: de Jager
authors.forename: Anna
authors.initials: A
authors.lastname: Carrano
authors.forename: Alexandra A M
authors.initials: AA
authors.lastname: Versleijen
authors.forename: Robert
authors.initials: R
authors.lastname: Veerhuis
authors.forename: Wilbert
authors.initials: W
authors.lastname: Boelens
authors.forename: Annemieke J M
authors.initials: AJ
authors.lastname: Rozemuller
authors.forename: Robert M W
authors.initials: RM
authors.lastname: de Waal
authors.forename: Marcel M
authors.initials: MM
authors.lastname: Verbeek
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D050886:HSP20 Heat-Shock Proteins / Q000502:physiology; D055551:HSP27 Heat-Shock Proteins / Q000502:physiology; D006360:Heat-Shock Proteins / Q000502:physiology; D050888:Heat-Shock Proteins, Small / Q000502:physiology*; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D008297:Male; D018832:Molecular Chaperones; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D050886:HSP20 Heat-Shock Proteins; D055551:HSP27 Heat-Shock Proteins; C442250:HSPB2 protein, human; C116424:HSPB3 protein, human; C413214:HSPB8 protein, human; D006360:Heat-Shock Proteins; D050888:Heat-Shock Proteins, Small; D018836:Inflammation Mediators; D018832:Molecular Chaperones; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases