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Experimental Genetics Group
Neurobiol Aging. 2007 Aug;28(8):1221-30. Thal DR1*, Larionov S1, Abramowski D2, Wiederhold KH2, Van Dooren T3, Yamaguchi H4, Haass C5, Van Leuven F3, Staufenbiel M2, Capetillo-Zarate E1. 1Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany. 2Novartis Institutes for Biomedical Research Basel, Basel, Switzerland. 3Department of Human Genetics, Katholieke Universiteit Leuven, Leuven, Belgium. 4Gunma University School of Health Sciences, Gunma, Japan. 5Department of Biochemistry, Adolf-Butenandt Institute, Ludwig Maximilians University, Munich, Germany. *Corresponding author. 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.  FULL TEXT |
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