engleski

Relationships of zinc and copper CSF levels and APOE genotype in Alzheimer's disease

Apolipoprotein E (ApoE) protein is involved in transport of cholesterol. In the brain it is mainly produced by astrocytes. The human APOE gene exists as three polymorphic alleles—ε2, ε3 and ε4—which have a worldwide frequency of 8.4%, 77.9% and 13.7%, respectively. However, the frequency of the ε4 allele is dramatically increased to about 40% in patients with late- onset Alzheimer’s disease (LOAD). The ApoE isoform-dependent promotion of LOAD may be explained by the ApoE-isoform-dependent ability (ApoE3 > ApoE4) to generate lipoprotein-like particles, which supply cholesterol to neurons. When brain cholesterol homeostasis is compromised with aging (supposedly by increased levels of oligomeric Aβ or oxysterols, both of which reduce cellular cholesterol level), supply of cholesterol to neurons via lipoprotein-like particles from glial cells of APOE3 genotype may be greater than that of APOE4 genotype. Since they interact with ApoE, an imbalance in the levels of transition metals like Cu, Zn and Fe reported in LOAD brains may be associated with disturbances in cholesterol metabolism. Two proposed mechanisms on how metal-ApoE interaction could lead to pathology in AD are: 1) Cu, Zn, and Fe accumulate in senile plaques, creating metal dyshomeostasis in AD that causes decrease in APOE transcription and translation (with consequent decrease of Aβ clearance), and 2) since metals stabilize ApoE isoforms in the order E2>E3>E4, the ApoE proteolysis that occurs in LOAD is more prominent for APOE4 carriers. The aims of this study were to assess the diagnostic potential of Cu and Zn levels in CSF (with and without APOE genotype) in differentiating AD patients from the group of patients with mild cognitive impairment (MCI) and cognitively healthy controls (HC). We found mean Zn levels in CSF significantly greater in APOE ε4 homozygotes (ε4/ε4) in comparison to APOE ε4- negative group both in the AD alone and across all groups (AD, MCI and HC) analyzed together. Additionally, mean Zn levels in CSF were significantly greater in ε4/ε4 patients in comparison to the ε3/ε3 group across all groups and in ε4/ε3 compared to ε4/ε2 group (in the AD group). Although these results should be validated on larger cohorts of patients and cognitively control subjects, we concluded that measurement of Zn levels in CSF in combination with APOE genotype has diagnostic potential for AD. This work was supported by the Croatian Science Foundation grant. no. IP-2014-09-9730.

Zinc ; copper ; APOE genotype

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