title: Occurrence and co-localization of amyloid beta-protein and apolipoprotein E in perivascular drainage channels of wild-type and APP-transgenic mice.
abstract: The deposition of the amyloid beta-protein (Abeta) is a hallmark of Alzheimer's disease (AD). One reason for Abeta-accumulation and deposition in the brain may be an altered drainage along perivascular channels. Extracellular fluid is drained from the brain towards the cervical lymph nodes via perivascular channels. The perivascular space around cerebral arteries is the morphological correlative of these drainage channels. Here, we show that Abeta is immunohistochemically detectable within the perivascular space of 25 months old wild-type and amyloid precursor protein (APP)-transgenic mice harboring the Swedish double mutation driven by a neuron specific promoter. Only small amounts of Abeta can be detected immunohistochemically in the perivascular space of wild-type mice. Cerebrovascular and parenchymal Abeta-deposits were absent. In APP-transgenic mice, large amounts of Abeta were found in the perivascular drainage channels accompanied with cerebrovascular and parenchymal Abeta-deposition. The apolipoprotein E (apoE) immunostaining within the perivascular channels did not vary between wild-type and APP-transgenic mice. Almost 100% of the area that represents the perivascular space was stained with an antibody directed against apoE. Here, Abeta co-localized with apoE indicating an involvement of apoE in the perivascular clearance of Abeta. Fibrillar congophilic amyloid was not seen in wild-type mice. In APP-transgenic animals, congophilic fibrillar amyloid material was seen in the wall of cerebral blood vessels but not in the perivascular space. In conclusion, our results suggest that non-fibrillar forms of Abeta are drained along perivascular channels and that apoE is presumably involved in this clearance mechanism. Overloading such a clearance mechanism in APP-transgenic mice appears to result in insufficient Abeta-clearance, increased Abeta-levels in the brain and the perivascular drainage channels, and finally in Abeta-deposition. In so doing, our results strengthen the hypothesis that an alteration of perivascular drainage supports Abeta-deposition and the development of AD.
authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany. Dietmar.Thal@uni-bonn.de <Dietmar.Thal@uni-bonn.de>
authors.forename: Dietmar Rudolf
authors.initials: DR
authors.lastname: Thal
authors.forename: Sergey
authors.initials: S
authors.lastname: Larionov
authors.forename: Dorothee
authors.initials: D
authors.lastname: Abramowski
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wiederhold
authors.forename: Tom
authors.initials: T
authors.lastname: Van Dooren
authors.forename: Haruyasu
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
authors.forename: Matthias
authors.initials: M
authors.lastname: Staufenbiel
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Capetillo-Zarate
mesh_terms: D000375:Aging / Q000378:metabolism; D000682:Amyloid / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D030801:Animals, Genetically Modified; D001057:Apolipoproteins E / Q000378:metabolism*; D002552:Cerebral Ventricles / Q000033:anatomy & histology / Q000378:metabolism* / Q000648:ultrastructure; D002560:Cerebrovascular Circulation; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008854:Microscopy, Electron / Q000379:methods; D008954:Models, Biological; D009154:Mutation
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E