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Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double A beta in human A betaPP transgenic mice.

Davis J, Xu F, Miao J, Previti ML, Romanov G, Ziegler K, Van Nostrand WE

Department of Medicine, Health Sciences Center, Stony Brook University, HSC T-15/083, Stony Brook, NY 11794-8153, USA.

Cerebral amyloid angiopathy (CAA) is a prominent pathological feature of Alzheimer's disease and related familial CAA disorders. However, the mechanisms that account for the cerebral vascular accumulation of amyloid beta-peptide (A beta) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human A beta precursor (A betaPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular A beta. Deficient clearance of Dutch/Iowa mutant A beta from brain across the capillary blood-brain barrier into the circulation may contribute to its potent cerebral accumulation. To further evaluate this theory, we generated a new transgenic mouse (Tg-Sw) that is nearly identical to Tg-SwDI, except lacking the Dutch/Iowa A beta mutations. Tg-Sw and Tg-SwDI mice expressed comparable levels of human A betaPP in brain and not in peripheral tissues. However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant A beta in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type A beta. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant A beta in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type A beta in plasma. Together, these findings suggest that while wild-type A beta is readily transported out of brain into plasma, Dutch/Iowa mutant A beta is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.

Published 22 May 2006 in Neurobiol Aging, 27(7): 946-54.
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