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ASN NEURO (2009) 1(2):art:e00006.doi:10.1042/AN20090015

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Memory deficits in APP23/Abca1^+/− mice correlate with the level of Aβ oligomers

Iliya Lefterov*¹, Nicholas F Fitz*, Andrea Cronican*, Preslav Lefterov*, Matthias Staufenbiel† and Radosveta Koldamova*¹

^*Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15219, U.S.A.
^†Department of Nervous System, Novartis Institutes of Biomedical Research, CH4002 Basel, Switzerland

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 Aβ 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 Aβ (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 A11-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 Aβ*56, as well as other low-molecular-mass Aβ 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 Aβ oligomers deposited in the hippocampus.

Key words: ABCA1, Abca1-knockout mouse, Alzheimer's disease, amyloid β protein, apolipoprotein E (ApoE), APP transgenic mouse

Abbreviations: Aβ, amyloid β protein, ABCA1, ATP-binding cassette transporter 1, AD, Alzheimer's disease, ApoE, apolipoprotein E, APP, amyloid precursor protein, CNS, central nervous system, DAPI, 4′,6-diamidino-2-phenylindole, GFAP, glial fibrillary acidic protein, HDL, high-density lipoprotein, LXR, liver X receptor, MWM, Morris Water Maze, PBST, PBS containing 0.2% Triton X-100, Thio-S, thioflavin S, X-34, 1,4-bis(3-carboxy-4-hydroxyphenylethenyl)-benzene

¹Correspondence may be addressed to either of these authors (email iliyal@pitt.edu or radak@pitt.edu).

Received 19 February 2009/19 March 2009; accepted 31 March 2009

Published as ASN NEURO Immediate Publication 31 March 2009, doi:10.1042/AN20090015

©2009 The Author(s) This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Licence (http://creativecommons.org/licenses/by-nc/2.5/) which permits unrestricted non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.