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.