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

Abstract

Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimer's disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.

Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

“…The effects of the APOE genotype and HFD on apoE lipidation in the brain were assessed via blue native gel, and the results can be seen in Figure 5C, n = 3 lanes per group, where each lane represents a pull of three mice from the same group. In accordance with previous findings [70,72], under control diet conditions, apoE4 mice displayed hypolipidation of apoE relative to apoE3 mice. Importantly, the extent of lipidation of apoE in apoE3 and apoE4 mice was increased in mice exposed to the HFD, rendering the lipidation of apoE4 HFD mice similar to that of the apoE3 control diet mice.…”

“…Further evidence supporting CNS processes as a driving force for the observed behavioral effects of the APOE genotype and diet was obtained by measurements of the apoE levels and lipidation. As previously shown, in both the brain and plasma, the levels of apoE in apoE4 mice are significantly lower than in apoE3 mice under basal conditions, effects that are accompanied by hypolipidation of brain apoE in apoE4 mice relative to apoE3 mice [71,72,76]. Interestingly, brain apoE levels were sensitive to both the APOE genotype and diet, seeing that the HFD reduced apoE levels in apoE3 mice, rendering them similar to apoE4 mice, which were not affected by the diet.…”

“…In conclusion, the present findings that apoE4 stimulates diabetic-related effects, such as an increase in glucose tolerance and insulin resistance and a decrease in insulin secretion, which are associated with further downstream distinct brain pathologies, and that apoE3 under pro-diabetic conditions of the HFD induces similar pathological changes, suggest that diabetic mechanisms play an important role in mediating the effects of apoE4 on brain pathology. This implies that diabetic-related therapy may be helpful in counteracting the effects of apoE4 in AD and that anti-apoE4-related therapies [72,100] may be beneficial in blocking the neuropathological effects of T2DM in apoE4 carriers.…”

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.…”

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

“…Intraperitoneal injection of CS-6253 into APOE4 TR mice 1) upregulated Abca1; 2) induced lipidation of APOE4; and 3) reduced cognitive deficits, tau hyperphosphorylation and Aβ accumulation [125]. In a follow-up study using APOE4 TR and APOE3 TR mice, the authors showed that CS-6253 also normalizes plasma APOE4 lipidation and stability to match APOE3 mice and additionally, this peptide was able to partially normalize plasma apoA-I and apoJ levels in APOE4 TR mice [126]. Another strategy to upregulate Abca1 is by using ASOs against microRNA-33.…”