Neurobiology of Aging 27 (2006) 946–954 Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Aß in human AßPP transgenic mice Judianne Davis, Feng Xu, Jianting Miao, Mary Lou Previti, Galina Romanov, Kelly Ziegler, William E. Van Nostrand ∗ Department of Medicine, Health Sciences Center, Stony Brook University, HSC T-15/083, Stony Brook, NY 11794-8153, USA Received 22 February 2005; received in revised form 5 May 2005; accepted 11 May 2005 Available online 18 August 2005 Abstract 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. © 2005 Elsevier Inc. All rights reserved. Keywords: Amyloid ß-peptide; Amyloid precursor protein; Cerebral amyloid angiopathy; Transgenic mice; Clearance; Plasma 1. Introduction Alzheimer’s disease (AD) and related disorders are char- acterized by the pathological accumulation of amyloid ß- peptides (Aß) in brain [24]. Aß peptides, which possess a high propensity to self-assemble into ß sheet-rich fibrils, are derived through proteolytic processing of the amyloid ß-peptide precursor (AßPP) by ß- and -secretase activities [24]. In AD, the primary site of Aß accumulation is in brain parenchymal plaques. Aß plaques can exist as either dif- fuse or fibrillar deposits. Another prominent site of brain Aß deposition occurs in and along the walls of cerebral blood vessels, a condition known as cerebral amyloid angiopathy ∗ Corresponding author. Tel.: +1 631 444 1661; fax: +1 631 444 2560. E-mail address: William.VanNostrand@stonybrook.edu (W.E. Van Nostrand). (CAA) [13,35,36]. In contrast to plaques, cerebral vascular Aß deposits appear to be exclusively fibrillar in nature. CAA is the prominent pathological feature of several familial disor- ders involving specific point mutations within the mid-region of the Aß domain of AßPP including the Dutch E22Q, Ital- ian E22K, and Iowa D23N substitutions [11,12,16,26,29]. Although these mutations do not appreciably affect the gen- eration of Aß, numerous in vitro studies have shown that they significantly enhance the fibrillogenic and cerebral vascular cytotoxic properties of Aß [4,17,18,32–34,41]. Recently, we generated transgenic mice that express neu- ronally derived human AßPP, harboring the Dutch-type and Iowa-type familial CAA mutations [5]. These mice were shown to develop early-onset and robust deposition of cere- bral microvascular amyloid and diffuse parenchymal Aß. This dramatic accumulation of cerebral Aß was accomplished despite the low expression of transgene encoded human 0197-4580/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2005.05.031