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

First Author  Davis J Year  2006
Journal  Neurobiol Aging Volume  27
Issue  7 Pages  946-54
PubMed ID  16105708 Mgi Jnum  J:108851
Mgi Id  MGI:3625200 Doi  10.1016/j.neurobiolaging.2005.05.031
Citation  Davis J, et al. (2006) Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Ass in human AssPP transgenic mice. Neurobiol Aging 27(7):946-54
abstractText  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 ss-peptide (Ass) have not been defined. Recently, we reported novel transgenic mice (Tg-SwDI) expressing neuronally derived Swedish/Dutch/Iowa vasculotropic mutant human Ass precursor (AssPP) that develop early-onset and robust accumulation of fibrillar cerebral microvascular Ass. Deficient clearance of Dutch/Iowa mutant Ass 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 Ass mutations. Tg-Sw and Tg-SwDI mice expressed comparable levels of human AssPP in brain and not in peripheral tissues. However, Tg-SwDI mice strongly accumulated Dutch/Iowa mutant Ass in brain, particularly in the cerebral microvasculature, whereas Tg-Sw mice exhibited no accumulations of wild-type Ass. Conversely, Tg-SwDI mice had no detectable Dutch/Iowa mutant Ass in plasma whereas Tg-Sw mice exhibited consistent levels of human wild-type Ass in plasma. Together, these findings suggest that while wild-type Ass is readily transported out of brain into plasma, Dutch/Iowa mutant Ass is deficient in this clearance process, likely contributing to its robust accumulation in the cerebral vasculature.
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