Neuroinflammation and blood-brain barrier changes in capillary amyloid angiopathy.
BACKGROUND
β-Amyloid (Aβ) accumulation in cortical capillaries is a variant of cerebral amyloid angiopathy (CAA) referred to as capillary CAA (capCAA). capCAA is associated with a neuroinflammatory response. In vitro studies indicate that Aβ induces reactive oxygen species (ROS) production, mainly generated through NADPH oxidase (NOX), by activated microglia. ROS in turn can induce altered expression of tight junctions (TJ), which are essential for blood-brain barrier (BBB) function. Whether the function of the BBB is affected in the brains of Alzheimer's disease (AD) patients with comorbid capCAA remains elusive. Cases with capCAA and no other AD-related changes allow studying capCAA-associated BBB alterations independent of AD pathology.


OBJECTIVE
In this study, we have investigated BBB alterations in capCAA and addressed the role of the neuroinflammatory response.


METHODS
Human postmortem brain tissue with capCAA was analyzed by immunohistochemical staining.


RESULTS
In this study, we show for the first time a dramatic loss of TJ proteins claudin-5, occludin and ZO-1 in Aβ-laden capillaries. In addition, affected capillaries are associated with clusters of NOX-2-positive activated microglia. Disrupted BBB function was observed by increased presence of fibrinogen around the affected capillaries.


CONCLUSIONS
Our data provide support for the early observation that neuroinflammatory response is involved in the altered expression of TJs in endothelial cells and loss of BBB integrity in capCAA.
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands. a.carrano @ vumc.nl
Anna
A
Carrano
Jeroen J M
JJ
Hoozemans
Saskia M
SM
van der Vies
Jack
J
van Horssen
Helga E
HE
de Vries
Annemieke J M
AJ
Rozemuller
D016229:Amyloid beta-Peptides / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology*; D001921:Brain / Q000473:pathology*; D002196:Capillaries / Q000378:metabolism / Q000473:pathology*; D016657:Cerebral Amyloid Angiopathy / Q000150:complications* / Q000473:pathology*; D062507:Claudin-5; D057167:Claudins / Q000378:metabolism; D015331:Cohort Studies; D004660:Encephalitis / Q000150:complications / Q000209:etiology* / Q000473:pathology; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D019255:NADPH Oxidases; D062793:Occludin; D010750:Phosphoproteins / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism / Q000473:pathology; D062826:Zonula Occludens-1 Protein
D016229:Amyloid beta-Peptides; D001798:Blood Proteins; C107466:CLDN5 protein, human; D062507:Claudin-5; D057167:Claudins; D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; D010750:Phosphoproteins; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D005340:Fibrinogen; D019255:NADPH Oxidases