ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

Abstract

The cholesterol transpoter ATP-binding cassette transporter A1 (ABCA1) moves lipids onto apolipoproteins including apolipoprotein E (apoE), which is the major cholesterol carrier in the brain and an established genetic risk factor for late-onset Alzheimer disease (AD). In amyloid mouse models of AD, ABCA1 deficiency exacerbates amyloidogenesis, whereas ABCA1 overexpression ameliorates amyloid load, suggesting a role for ABCA1 in A␤ metabolism. Agonists of liver X receptors (LXR), including GW3965, induce transcription of several genes including ABCA1 and apoE, and reduce A␤ levels and improve cognition in AD mice. However, the specific role of ABCA1 in mediating beneficial responses to LXR agonists in AD mice is unknown. We evaluated behavioral and neuropathogical outcomes in GW3965-treated female APP/PS1 mice with and without ABCA1. Treatment of APP/PS1 mice with GW3965 increased ABCA1 and apoE protein levels. ABCA1 was required to observe significantly elevated apoE levels in brain tissue and cerebrospinal fluid upon therapeutic (33 mg/kg/day) GW3965 treatment. At 33 mg/kg/day, GW3965 was also associated with a trend toward redistribution of A␤ to the carbonate-soluble pool independent of ABCA1. APP/PS1 mice treated with either 2.5 or 33 mg/kg/day of GW3965 showed a clear trend toward reduced amyloid burden in hippocampus and whole brain, whereas APP/ PS1-treated mice lacking ABCA1 failed to display reduced amyloid load in the whole brain and showed trends toward increased hippocampal amyloid. Treatment of APP/PS1 mice with either dose of GW3965 completely restored novel object recognition memory to wild-type levels, which required ABCA1. These results suggest that ABCA1 contributes to several beneficial effects of the LXR agonist GW3965 in APP/PS1 mice.Lipid metabolism is increasingly recognized to play a key role in the pathogenesis of Alzheimer disease (AD), 4 which is the leading cause of dementia in the elderly (1). AD is characterized by the presence of two neuropathological hallmarks including extracellular amyloid plaques that consist mainly of aggregated A␤ peptides and intracellular neurofibrillary tangles consisting of hyperphosphorylated Tau protein (2). Although the pathogenesis of AD is not completely understood, a leading hypothesis is that aberrant metabolism of A␤ peptides, which are derived by proteolytic cleavage from amyloid precursor protein (APP), triggers many of the toxic events in AD and eventually leads to both Tau and amyloid pathologies (3). Less than 5% of AD patients exhibit disease onset in their 40s and 50s due to genetic mutations that lead to increased production of A␤ peptides, particularly of the most detrimental A␤42 species (4). The cause of AD in more than 95% of subjects that typically develop AD in late life is unknown. As production of A␤ is generally not altered in these patients, age-related defects in A␤ degradation and clearance is emerging as a leading hypothesis for development of AD in the majority of patients (5).In mice, apoE exists in only one allelic state, ...

Characterization of AD-like phenotype in aged APPSwe/PS1dE9 mice

“…This presumption is supported by the presence of only mature fibrillary plaques, without new inflammatory plaques, in the hippocampus of 24-month-old APP/PS1 mice. Similar to adult APP/PS1 mice, the deposition of Aβ plaques was mainly present in the molecular layer and stratum lacunosum moleculare, while being virtually absent in the pyramidal cell layer and the granule cell layer (Bas Orth et al 2005;Oksman et al 2006;Donkin et al 2010;Scott et al 2012;Xu et al 2012Xu et al , 2016. Furthermore, our previous and present results suggest that laminar heterogeneity and Aβ load is correlated with laminar variability in expression of APP secretases (Xu et al 2016).…”

Hormonal modulators of glial ABCA1 and apoE levels

“…Synthetic LXR agonists, including TO901317 and GW3965, cross the blood brain barrier and stimulate expression of many target genes, including ABCA1 and apoE (39)(40)(41)(42). Treatment of multiple AD mouse models with TO901317 or GW3965 consistently improves memory and reduces A ␤ levels (39)(40)(41)(42).…”

“…Importantly, LXR agonists show considerable effi cacy in maintaining cognitive function in several AD mouse models (39)(40)(41)(42). Synthetic LXR agonists, including TO901317 and GW3965, cross the blood brain barrier and stimulate expression of many target genes, including ABCA1 and apoE (39)(40)(41)(42).…”

Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

“…Selective exploration of the novel object is taken as evidence that the preexposed object is recognised as familiar. This widely-used task has revealed deficits in a wide range of different 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 transgenic models of AD [32], and impairments are routinely observed in older APPswe/PS1dE9 mice [33,34,35,36,37; but see 38]. SOR deficits are also occasionally reported in these mice at 6-7 months of age [34,39,40,41], but never in animals younger than 6 months [40,42].…”