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.

Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins

“…This was performed with the hippocampal extracts, whereas the plasma samples were subjected to fast protein liquid chromatography (FPLC) as described below. Accordingly, the hippocampal homogenates were electrophoresed on 4–16% gels in the Native PAGE Novex Bis-Tris Gel System purchased from Novex and according to the manufacturer's instructions, as previously described [7, 25]. Gels were next transferred to PVDF membranes and stained with either goat anti-apoE Ab (1:10,000; Millipore), rabbit anti-apoA-I Ab (1:1000; Meridian Life Science, Inc.), or goat anti-apoJ Ab (1:1000; Santa Cruz).…”

“…injections of the ABCA1-agonist peptide CS-6253 results in the accumulation of the peptide in the brain and in reversal of the hypolipidation of brain apoE4 which is observed in the non-treated mice [25]. Importantly, these effects were associated with reversal of the brain pathological effects of apoE4 and of the corresponding apoE4-driven cognitive impairments [25]. …”

Astrocytic transporters in Alzheimer's disease

“…The use of a small molecule ABCA1 agonist (CS-6253) has produced some interesting results both in vitro and in vivo. In vivo studies highlight that injection of the CS-6253 peptide can restore cognitive deficits in APOE transgenic mice (245), and the peptide can modulate both central and peripheral lipid metabolism (246). This gives a clear indication that ABCA1 transporters can reverse cognitive decline, through modulation of ApoE4.…”

[P3–317]: DHA BRAIN UPTAKE AND APOE4 STATUS: A PET STUDY WITH [1‐11C]‐DHA

“…From plasma samples collected at 0, 3,7,10,15,20,40, and 60 minutes after infusion of [1-11 C]-DHA, total lipids were extracted into chloroform:methanol (1:1) as previously described [24].…”

“…In the brain, APOE forms high-density lipoprotein particles and participates in exchange of lipids between glial cells and neurons [2]. Clinical and animal studies indicate that brain APOE particle size and number differ by APOE genotype [3][4][5]. In plasma, APOE4 is catabolized faster with a plasma residence time of approximately half that of APOE3 [6].…”