Searching for just a few words should be enough to get started. If you need to make more complex queries, use the tips below to guide you.
Article type: Research Article
Authors: Boehm-Cagan, Anata | Bar, Ronia | Liraz, Oria | Bielicki, John K.b | Johansson, Jan O.c | Michaelson, Daniel M.a; *
Affiliations: [a] The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel | [b] Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA | [c] Artery Therapeutics, Inc., San Ramon, CA, USA
Correspondence: [*] Correspondence to: Daniel M. Michaelson, The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Ramat Aviv 6997801, Tel Aviv, Israel. Tel.: +972 3 6409624; Fax: +972 3 6406356; E-mail: [email protected].
Abstract: The allele ɛ4 of apolipoprotein E (apoE4) is the most prevalent genetic risk factor for Alzheimer’s disease (AD) and is therefore a promising therapeutic target. Human and animal model studies suggest that apoE4 is hypolipidated; accordingly, we have previously shown that the retinoid X receptor (RXR) agonist bexarotene upregulates ABCA1, the main apoE-lipidating protein, resulting in increased lipidation of apoE4, and the subsequent reversal of the pathological effects of apoE4, namely: accumulation of Aβ42 and hyperphosphorylated tau, as well as reduction in the levels of synaptic markers and cognitive deficits. Since the RXR system has numerous other targets, it is important to devise the means of activating ABCA1 selectively. We presently utilized CS-6253, a peptide shown to directly activate ABCA1 in vitro, and examined the extent to which it can affect the degree of lipidation of apoE4 in vivo and counteract the associated brain and behavioral pathologies. This revealed that treatment of young apoE4-targeted replacement mice with CS-6253 increases the lipidation of apoE4. This was associated with a reversal of the apoE4-driven Aβ42 accumulation and tau hyperphosphorylation in hippocampal neurons, as well as of the synaptic impairments and cognitive deficits. These findings suggest that the pathological effects of apoE4 in vivo are associated with decreased activation of ABCA1 and impaired lipidation of apoE4 and that the downstream brain-related pathology and cognitive deficits can be counteracted by treatment with the ABCA1 agonist CS-6253. These findings have important clinical ramifications and put forward ABCA1 as a promising target for apoE4-related treatment of AD.
Keywords: ABCA1, Alzheimer’s disease, apoE, CS-6253, lipidation, lipids
DOI: 10.3233/JAD-160467
Journal: Journal of Alzheimer's Disease, vol. 54, no. 3, pp. 1219-1233, 2016
IOS Press, Inc.
6751 Tepper Drive
Clifton, VA 20124
USA
Tel: +1 703 830 6300
Fax: +1 703 830 2300
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
IOS Press
Nieuwe Hemweg 6B
1013 BG Amsterdam
The Netherlands
Tel: +31 20 688 3355
Fax: +31 20 687 0091
[email protected]
For editorial issues, permissions, book requests, submissions and proceedings, contact the Amsterdam office [email protected]
Inspirees International (China Office)
Ciyunsi Beili 207(CapitaLand), Bld 1, 7-901
100025, Beijing
China
Free service line: 400 661 8717
Fax: +86 10 8446 7947
[email protected]
For editorial issues, like the status of your submitted paper or proposals, write to [email protected]
如果您在出版方面需要帮助或有任何建, 件至: [email protected]