Apolipoprotein E, Especially Apolipoprotein E4, Increases the Oligomerization of Amyloid β Peptide

Abstract

Alzheimer’s disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid β peptide (Aβ) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE ε4) allele is known to be a genetic risk factor for developing AD. However it is still unknown how apoE impacts the process of Aβ oligomerization. Here, we found that the level of Aβ oligomers in APOEε4/ε4 AD patient brains is 2.7 times higher than those in APOEε3/ε3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of Aβ oligomers. To test this hypothesis, we examined apoE’s effect on Aβ oligomer formation. Using both synthetic Aβ and a split-luciferase method for monitoring Aβ oligomers, we observed that apoE increased the level of Aβ oligomers in an isoform dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE carboxy-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of Aβ oligomers. Taken together, these data show that lipidated apoE, especially apoE4, increases Aβ oligomers in the brain. Higher levels of Aβ oligomers in the brains of APOEε4/ε4 carriers compared to APOEε3/ε3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.

ApoE gene and exceptional longevity: Insights from three independent cohorts

“…There is strong evidence that ApoE ε4 facilitates Aβ deposition, with senile plaque density being significantly higher in the brains of AD ε4/ε4 patients compared with those with the ε3/ε3 genotype (Gomez-Isla et al, 1996;Rebeck et al, 1993). Although Aβ deposition is the pathological hallmark of AD, oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component, in which higher levels of Aβ oligomers are increasing the loss of dendritic spines and accelerating memory impairments in AD (Hashimoto et al, 2012;Wu et al, 2010). With regards to this, a recent study showed that the levels of Aβ oligomers in AD patients were lowest in those carrying the ε2-allele (Hashimoto et al, 2012).…”

“…Although Aβ deposition is the pathological hallmark of AD, oligomeric, soluble forms of Aβ have been implicated as the synaptotoxic component, in which higher levels of Aβ oligomers are increasing the loss of dendritic spines and accelerating memory impairments in AD (Hashimoto et al, 2012;Wu et al, 2010). With regards to this, a recent study showed that the levels of Aβ oligomers in AD patients were lowest in those carrying the ε2-allele (Hashimoto et al, 2012). The ε2-allele also seems to play a protective role against CVD (Bennet et al, 2007;Gerdes et al, 2000;Kolovou et al, 2002), though the evidence is probably weaker than for negative effect of the ε4-allele (Drenos and Kirkwood, 2010).…”

Amyloid-β Pathology and APOE Genotype Modulate Retinoid X Receptor Agonist Activity in Vivo

“…the apoE/A␤ complex. In vivo, apoE isoform specifically modulates A␤ clearance (63)(64)(65)(66)(67)(68)(69), with soluble A␤ clearance lower with apoE4 compared with apoE3. Furthermore, NR agonists increase A␤ degradation in vitro in an ABCA1 and apoE-dependent manner (63).…”

Blocking the apoE/Aß interaction ameliorates Aß-related pathology in APOE ¿2 and ¿4 targeted replacement Alzheimer model mice

“…In addition to a marked reduction in Aβ deposition in Aβ12-28P-treated mice, we also noticed a significant reduction in the level of Aβ oligomers. It has been recently appreciated that apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers [33,34]. Although it appears that enhanced Aβ oligomerization occurs in settings of elevated Aβ x-42 level, which is associated with the apoE4 background, there is experimental evidence to indicate that direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly and that all three isoforms promote this process in the rank order E4 > E3 > E2 [33].…”

“…It has been recently appreciated that apoE, especially its apoE4 isoform, facilitates the formation of Aβ oligomers [33,34]. Although it appears that enhanced Aβ oligomerization occurs in settings of elevated Aβ x-42 level, which is associated with the apoE4 background, there is experimental evidence to indicate that direct interaction between apoE and Aβ facilitates Aβ oligomeric assembly and that all three isoforms promote this process in the rank order E4 > E3 > E2 [33]. Reduced Aβ oligomer level following from disrupted apoE/Aβ binding appears to provide further evidence that the direct apoE/Aβ interaction enhances oligomeric assembly of Aβ and that treatment with an apoE/Aβ inhibitor is beneficial for preventing Aβ oligomerization and for ameliorating synaptotoxicty related to Aβ oligomers.…”