title: ABCA1 Agonist Reverses the ApoE4-Driven Cognitive and Brain Pathologies.
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.
authors: The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors: Anat
authors: A
authors: Boehm-Cagan
authors: The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors: Roni
authors: R
authors: Bar
authors: The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors: Ori
authors: O
authors: Liraz
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA, USA.
authors: John K
authors: JK
authors: Bielicki
authors: Artery Therapeutics, Inc., San Ramon, CA, USA.
authors: Jan O
authors: JO
authors: Johansson
authors: The Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors: Daniel M
authors: DM
authors: Michaelson
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000819:agonists* / Q000378:metabolism; D000818:Animals; D053327:Apolipoprotein E4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D003072:Cognition Disorders / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D064286:ATP Binding Cassette Transporter 1; D053327:Apolipoprotein E4; D010455:Peptides; C577833:Abca1 protein, mouse; C000607327:CS-6253
keywords: ABCA1; Alzheimer’s disease; CS-6253; apoE; lipidation; lipids