Journal of Alzheimer’s Disease 31 (2012) 359–369 DOI 10.3233/JAD-2012-120421 IOS Press 359 Human Apolipoprotein E2 Promotes Parenchymal Amyloid Deposition and Neuronal Loss in Vasculotropic Mutant Amyloid- Protein Tg-SwDI Mice Feng Xu a , Michael P. Vitek b , Carol A. Colton b , Mary Lou Previti a , Judianne Davis a and William E. Van Nostrand a,∗ a Department of Neurosurgery and Medicine, Stony Brook University, Stony Brook, NY, USA b Department of Medicine, Division of Neurology, Duke University Medical Center, Durham, NC, USA Handling Associate Editor: Marcel Verbeek Accepted 12 April 2012 Abstract. Human apolipoprotein (ApoE) genotype influences the development of Alzheimer’s disease and cerebral amyloid angiopathy (CAA), where the ε4 allele increases and the ε2 allele decreases the risk for developing disease. Specific mutations within the amyloid- (A) peptide have been identified that cause familial forms of CAA. However, the influence of APOE genotype on accumulation of CAA mutant A in brain is not well understood. Earlier, we showed that human ApoE4 redis- tributes fibrillar amyloid deposition from the cerebral microvasculature to parenchymal plaques in Tg-SwDI mice, a model that accumulates human Dutch/Iowa (E22Q/D23N) CAA mutant A in brain (Xu et al., J Neurosci 28, 5312-5320, 2008). Human ApoE2 can reduce A pathology in transgenic models of parenchymal plaques. Here we determined if human ApoE2 can influence the location and severity of amyloid pathology in Tg-SwDI mice. Comparing Tg-SwDI mice bred onto a human APOE2/2 or human APOE4/4 background, we found there was no change in the brain levels of total A 40 and A 42 compared to mice on the endogenous mouse APOE background. In Tg-SwDI mice on either human APOE background, there was a similarly strong reduction in the levels of microvascular CAA and emergence of extensive parenchymal plaque amyloid. In both Tg-SwDI-hAPOE2/2 and Tg-SwDI-hAPOE4/4 mice, the distribution of ApoE proteins and neuronal loss were associated with parenchymal amyloid plaques. These findings suggest that compared with human ApoE4, human ApoE2 does not benefi- cially influence the quantitative or spatial accumulation of human Dutch/Iowa CAA mutant amyloid or associated pathology in transgenic mice. Keywords: Alzheimer’s disease, amyloid  protein, apolipoprotein E, cerebral amyloid angiopathy, transgenic mice INTRODUCTION Alzheimer’s disease (AD) and related disorders are characterized by the pathological accumulation ∗ Correspondence to: Dr. William E. Van Nostrand, Depart- ment of Neurosurgery, HSC T-12/086, Stony Brook Univer- sity, Stony Brook, NY 11794-8122, USA. E-mail: William. VanNostrand@sbumed.org. of amyloid- peptides (A) in brain [1, 2]. A pep- tides, which possess a high propensity to self-assemble into  sheet-rich fibrils, are derived through sequential proteolytic processing of the amyloid- protein pre- cursor (APP) by - and -secretase activities [1, 2]. In AD, the primary site of A accumulation is in brain parenchymal plaques. However, another prominent location of brain A deposition occurs in and along ISSN 1387-2877/12/$27.50 © 2012 – IOS Press and the authors. All rights reserved