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Experimental Genetics Group
Am J Pathol, 2000 Oct;157(4):1283-1298. Van Dorpe J1, Smeijers L1, Dewachter I1, Nuyens D2, Spittaels K1, Van Den Haute C1, Mercken M3, Moechars D3, Laenen I1, Kuiperi C1, Bruynseels K1, Tesseur I1, Loos R4, Vanderstichele H5, Checler F6, Sciot R7, Van Leuven F1. 1Experimental Genetics Group, Center for Human Genetics, Flemish Institute for Biotechnology, Katholieke Universiteit Leuven, Leuven, Belgium. 2Center for Transgene Technology and Gene Therapy, K.U.Leuven, Leuven, Belgium. 3Janssen Research Foundation, Beerse, Belgium. 4Center for Molecular and Vascular Biology and Genetic Epidemiology, K.U.Leuven, Leuven, Belgium. 5Innogenetics, Gent, Belgium. 6Institut de Pharmacology Moléculaire et Cellulaire/CNRS, Valbonne, France. 7Department of Pathology, University Hospitals Leuven, Leuven, Belgium. Deposition of amyloid beta-peptide (Abeta) in cerebral vessel walls (cerebral amyloid angiopathy, CAA) is very frequent in Alzheimer's disease and occurs also as a sporadic disorder. Here, we describe significant CAA in addition to amyloid plaques, in aging APP/Ld transgenic mice overexpressing the London mutant of human amyloid precursor protein (APP) exclusively in neurons. The number of amyloid-bearing vessels increased with age, from approximately 10 to >50 per coronal brain section in APP/Ld transgenic mice, aged 13 to 24 months. Vascular amyloid was preferentially deposited in arterioles and ranged from small focal to large circumferential depositions. Ultrastructural analysis allowed us to identify specific features contributing to weakening of the vessel wall and aneurysm formation, ie, disruption of the external elastic lamina, thinning of the internal elastic lamina, interruption of the smooth muscle layer, and loss of smooth muscle cells. Biochemically, the much lower Abeta42:Abeta40 ratio evident in vascular relative to plaque amyloid, demonstrated that in blood vessel walls Abeta40 was the more abundant amyloid peptide. The exclusive neuronal origin of transgenic APP, the high levels of Abeta in cerebrospinal fluid compared to plasma, and the specific neuroanatomical localization of vascular amyloid strongly suggest specific drainage pathways, rather than local production or blood uptake of Abeta as the primary mechanism underlying CAA. The demonstration in APP/Ld mice of rare vascular amyloid deposits that immunostained only for Abeta42, suggests that, similar to senile plaque formation, Abeta42 may be the first amyloid to be deposited in the vessel walls and that it entraps the more soluble Abeta40. Its ability to diffuse for larger distances along perivascular drainage pathways would also explain the abundance of Abeta40 in vascular amyloid. Consistent with this hypothesis, incorporation of mutant presenilin-1 in APP/Ld mice, which resulted in selectively higher levels of Abeta42, caused an increase in CAA and senile plaques. This mouse model will be useful in further elucidating the pathogenesis of CAA and Alzheimer's disease, and will allow testing of diagnostic and therapeutic strategies.  FULL TEXT |
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