Abstract 399: Cell, Mice and Human CSF Studies Indicate Impaired Interactions Between ABCA-1 and ApoE4 in ApoE4 Driven Alzheimer’s Disease

Abstract

Background: Loss-of-function mutations in the ATP Binding Cassette A-1 (ABCA-1) transporter and the ApoE4 allele are associated with increased Alzheimer’s disease (AD) risk. We recently reported decreased ABCA-1 activity of cerebrospinal fluid (CSF) from participants with AD. Our aim is to study the interaction of ApoE4 with ABCA-1 activity in astrocytes, in human apoE4 (hApoE4) targeted replacement (TR) mice, and in CSF from humans grouped by APOE genotype. Methods: ABCA-1 expression and activity were assessed in astrocytes that express human ApoE isoforms and in hApoE mice. The ability of CSF to activate ABCA-1 was examined in cells. CSF from 59 older individuals with or without cognitive impairment was analyzed for ApoE particle size using native gel electrophoresis, and ABCA-1 cholesterol efflux activity. The effect of the ABCA-1 agonist CS-6253 on ABCA-1 activity and AD pathology was examined. Results: ApoE4 vs. apoE3 expressing astrocytes had decreased ABCA-1 expression that was associated with hypolipidated ApoE4. A similar discrepancy for ABCA-1 and apoE lipidation was found between hApoE4 and hApoE3 TR mice. CSF ApoE was resolved in four distinct bands by electrophoresis α 0 (>669 KDa), α 1 (600 KDa), α 2 (440 KDa) and α 3 (232-140 KDa). The amount of total ApoE present in α 0 size was reduced in ε4/ε4 vs ε3/ε3 individuals (3.208 % (SD 0.6156; N=3) vs 8.904 % (SD 0.6156; N=29), p<0.05), whereas total ApoE in α 2 size was increased in ε4/ε4 vs ε3/ε3 individuals (60.68 % (SD 8.207; N=3) vs 37.34 % (SD 16.80; N=31), p<0.05). CSF from ε4/ε4 individuals (N=3) has reduced capacity to induce ABCA-1 mediated cholesterol efflux compared to CSF from non ε4 individuals (N=9) (adjusted efflux 1.288 vs 1.594, p<0.05). CS6253 incubation with CSF increased ABCA1 mediated efflux in hApoE3 and hApoE4 TR mice, respectively. Treatment with the ABCA-1 agonist CS-6253 enhanced CSF cholesterol efflux capacity and reversed cognitive deficits in hApoE4 TR mice. Conclusions: ApoE4 was associated with reduced ABCA-1 activity and hypolipidated ApoE4 in vivo , in vitro and in CSF . The ABCA-1 agonist CS6253 improved apoE lipidation in astrocytes, CSF and in hApoE4 TR mice. The findings stress the importance of ABCA-1 in apoE4 driven AD and ABCA-1 activity of CSF as a biomarker in AD.