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Experimental Genetics Group
J Clin Invest. 2007 Nov;117(11):3453-62. Gevaert T1, Vriens J2, Segal A2, Everaerts W1, Roskams T3, Talavera K2, Owsianik G2, Liedtke W4, Daelemans D5, Dewachter I6, Van Leuven F6, Voets T2, De Ridder D1, Nilius B2. 1Department of Urology, University Hospital Gasthuisberg, Katholieke Universiteit Leuven, Leuven, Belgium. 2Department of Molecular Cell Biology, Division of Physiology, Laboratory of Ion Channel Research, Katholieke Universiteit Leuven, Leuven, Belgium. 3Department of Morphology and Molecular Pathology, Katholieke Universiteit Leuven, Leuven, Belgium. 4Center for Translational Neuroscience, Duke University Medical Center, Durham, North Carolina, USA. 5Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Katholieke Universiteit Leuven, Leuven, Belgium. 6Department of Human Genetics, Experimental Genetics Group, Katholieke Universiteit Leuven, Leuven, Belgium. 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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