Affiliation:
1. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, U.S.A.
2. Department of Nervous System, Novartis Institutes of Biomedical Research, CH-4002 Basel, Switzerland
Abstract
ABCA1, a member of the ATP-binding cassette family of transporters, lipidates ApoE (apolipoprotein A) and is essential for the generation of HDL (high-density lipoprotein)-like particles in the CNS (central nervous system). Lack of Abca1 increases amyloid deposition in several AD (Alzheimer's disease) mouse models. We hypothesized that deletion of only one copy of Abca1 in APP23 (where APP is amyloid precursor protein) AD model mice will aggravate memory deficits in these mice. Using the Morris Water Maze, we demonstrate that 2-year-old Abca1 heterozygous APP23 mice (referred to as APP23/het) have impaired learning during acquisition, and impaired memory retention during the probe trial when compared with age-matched wild-type mice (referred to as APP23/wt). As in our previous studies, the levels of ApoE in APP23/het mice were decreased, but the differences in the levels of A β and thioflavin-S-positive plaques between both groups were insignificant. Importantly, dot blot analysis demonstrated that APP23/het mice have a significantly higher level of soluble A11-positive A β (amyloid β protein) oligomers compared with APP23/wt which correlated negatively with cognitive performance. To confirm this finding, we performed immunohistochemistry with the A11 antibody, which revealed a significant increase of All-positive oligomer structures in the CA1 region of hippocampi of APP23/het. This characteristic region-specific pattern of A11 staining was age-dependent and was missing in younger APP23 mice lacking Abca1. In contrast, the levels of A β*56, as well as other low-molecular-mass A β oligomers, were unchanged among the groups. Overall, the results of the present study demonstrate that in aged APP23 mice memory deficits depend on Abca1 and are likely to be mediated by the amount of A β oligomers deposited in the hippocampus.
Subject
Clinical Neurology,General Neuroscience
Cited by
55 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献