Zinc affects the proteolytic stability of Apolipoprotein E in an isoform-dependent way

Abstract

The pathological role of zinc in Alzheimer's disease (AD) is not yet fully elucidated, but there is strong evidence that zinc homeostasis is impaired in the AD brain and that this contributes to disease pathogenesis. In this study we examined the effects of zinc on the proteolysis of synthetic Apolipoprotein E (ApoE), a protein whose allelic variants differentially contribute to the onset/progression of disease. We have demonstrated that zinc promotes the proteolysis (using plasma kallikrein, thrombin and chymotrypsin) of synthetic ApoE in an isoform-specific way (E4>E2 and E3), resulting in more ApoE fragments, particularly for ApoE4. In the absence of exogenous proteases there was no effect of metal modulation on either lipidated or non-lipidated ApoE isoforms. Thus, increased zinc in the complex milieu of the ageing and AD brain could reduce the level of normal full-length ApoE and increase other forms that are involved in neurodegeneration. We further examined human plasma samples from people with different ApoE genotypes. Consistent with previous studies, plasma ApoE levels varied according to different genotypes, with ApoE2 carriers showing the highest total ApoE levels and ApoE4 carriers the lowest. The levels of plasma ApoE were not affected by either the addition of exogenous metals (copper, zinc or iron) or by chelation. Taken together, our study reveals that zinc may contribute to the pathogenesis of AD by affecting the proteolysis of ApoE, which to some extent explains why APOE4 carriers are more susceptible to AD.

The effects of zinc supplementation on primary human retinal pigment epithelium

“…The association between APOE and zinc appears to be at multiple levels. APOE isoforms bind zinc directly [84], and this binding can increase their stability [85]. In addition, it is believed that zinc can increase cellular APOE levels by directly affecting transcription [86] and/or secretion [87].…”

APOE genotype and stress response - a mini review

“…Cell culture experiments revealed specifically APOE4 synthesized by neurons as being more prone to proteolytic cleavage compared with APOE3 [ 98 – 100 ]. Interestingly, zinc potently induced APOE4 proteolytic degradation in vitro [ 101 ] and, correspondingly, higher levels of zinc were detected previously in the serum of AD patients carrying the ε4 allele [ 101 , 102 ]. Specifically, APOE4 proteolytic fragmentation led to increased generation of neurotoxic C-terminally truncated fragments, particularly the fragment APOE (1-272) [ 98 , 99 ].…”

The essential elements of Alzheimer’s disease

“…There are several reports of zinc interacting also with the other major proteins implicated in AD. Zinc is reported to increase Presenilin 1 expression (108), and to affect the stability of apolipoprotein E (ApoE), particularly ApoE4 (109). Conversely, Presenilin 1 and ApoE expression have been reported to play essential roles in maintaining cellular and neuronal zinc trafficking (108,110).…”