title: Amyloid-β contributes to blood-brain barrier leakage in transgenic human amyloid precursor protein mice and in humans with cerebral amyloid angiopathy.
abstract: OBJECTIVE
  Cerebral amyloid angiopathy (CAA) is a degenerative disorder characterized by amyloid-β (Aβ) deposition in the blood-brain barrier (BBB). CAA contributes to injuries of the neurovasculature including lobar hemorrhages, cortical microbleeds, ischemia, and superficial hemosiderosis. We postulate that CAA pathology is partially due to Aβ compromising the BBB.
  
  
  METHODS
  We characterized 19 patients with acute stroke with "probable CAA" for neurovascular pathology based on MRI and clinical findings. Also, we studied the effect of Aβ on the expression of tight junction proteins and matrix metalloproteases (MMPs) in isolated rat brain microvessels.
  
  
  RESULTS
  Two of 19 patients with CAA had asymptomatic BBB leakage and posterior reversible encephalopathic syndrome indicating increased BBB permeability. In addition to white matter changes, diffusion abnormality suggesting lacunar ischemia was found in 4 of 19 patients with CAA; superficial hemosiderosis was observed in 7 of 9 patients. Aβ(40) decreased expression of the tight junction proteins claudin-1 and claudin-5 and increased expression of MMP-2 and MMP-9. Analysis of brain microvessels from transgenic mice overexpressing human amyloid precursor protein revealed the same expression pattern for tight junction and MMP proteins. Consistent with reduced tight junction and increased MMP expression and activity, permeability was increased in brain microvessels from human amyloid precursor protein mice compared with microvessels from wild-type controls.
  
  
  CONCLUSIONS
  Our findings indicate that Aβ contributes to changes in brain microvessel tight junction and MMP expression, which compromises BBB integrity. We conclude that Aβ causes BBB leakage and that assessing BBB permeability could potentially help characterize CAA progression and be a surrogate marker for treatment response.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors: Anika M S
authors: AM
authors: Hartz
authors: Björn
authors: B
authors: Bauer
authors: Emma L B
authors: EL
authors: Soldner
authors: Andrea
authors: A
authors: Wolf
authors: Sandra
authors: S
authors: Boy
authors: Roland
authors: R
authors: Backhaus
authors: Ivan
authors: I
authors: Mihaljevic
authors: Ulrich
authors: U
authors: Bogdahn
authors: Hans H
authors: HH
authors: Klünemann
authors: Gerhard
authors: G
authors: Schuierer
authors: Felix
authors: F
authors: Schlachetzki
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001812:Blood-Brain Barrier / Q000473:pathology*; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D002462:Cell Membrane / Q000473:pathology / Q000502:physiology; D016657:Cerebral Amyloid Angiopathy / Q000235:genetics* / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000209:etiology / Q000473:pathology; D005260:Female; D005456:Fluorescent Dyes; D006486:Hemosiderosis / Q000209:etiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D018579:Patient Selection; D010641:Phenotype; D020521:Stroke / Q000145:classification / Q000209:etiology; D019108:Tight Junctions / Q000473:pathology; D014057:Tomography, X-Ray Computed; D014966:Xanthenes
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D005456:Fluorescent Dyes; D014966:Xanthenes; C034657:Texas red; D020782:Matrix Metalloproteinases