Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa double AB in human AβPP transgenic mice

被引：48

作者：

Davis, Judianne ^{[1
]}

Xu, Feng ^{[1
]}

Miao, Jianting ^{[1
]}

Previti, Mary Lou ^{[1
]}

Romanov, Galina ^{[1
]}

Ziegler, Kelly ^{[1
]}

Van Nostrand, William E. ^{[1
]}

机构：

[1] SUNY Stony Brook, Hlth Sci Ctr, Dept Med, Stony Brook, NY 11794 USA

来源：

NEUROBIOLOGY OF AGING | 2006年 / 27卷 / 07期

关键词：

amyloid beta-peptide; amyloid precursor protein; cerebral amyloid angiopathy; transgenic mice; clearance; plasma;

D O I：

10.1016/j.neurobiolaging.2005.05.031

中图分类号：

R592 [老年病学]; C [社会科学总论];

学科分类号：

03 ; 0303 ; 100203 ;

摘要：

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 (ABPP) 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 ABPP 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. (c) 2005 Elsevier Inc. All rights reserved.

引用

页码：946 / 954

页数：9

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