Abstract
Alzheimer's disease (AD) is characterized by proteasome activity impairment, oxidative stress, and epigenetic changes, resulting in β-amyloid (Aβ) production/degradation imbalance. Apolipoprotein E (ApoE) is implicated in Aβ clearance, and particularly, the ApoE ε4 isoform predisposes to AD development. Regular physical activity is known to reduce AD progression. However, the impact of ApoE polymorphism and physical exercise on Aβ production and proteasome system activity has never been investigated in human peripheral blood cells, particularly in erythrocytes, an emerging peripheral model used to study biochemical alteration. Therefore, the influence of ApoE polymorphism on the antioxidant defences, amyloid accumulation, and proteasome activity was here evaluated in human peripheral blood cells depending on physical activity, to assess putative peripheral biomarkers for AD and candidate targets that could be modulated by lifestyle. Healthy subjects were enrolled and classified based on the ApoE polymorphism (by the restriction fragment length polymorphism technique) and physical activity level (Borg scale) and grouped into ApoE ε4/non-ε4 carriers and active/non-active subjects. The plasma antioxidant capability (AOC), the erythrocyte Aβ production/accumulation, and the nuclear factor erythroid 2-related factor 2 (Nrf2) mediated proteasome functionality were evaluated in all groups by the chromatographic and immunoenzymatic assay, respectively. Moreover, epigenetic mechanisms were investigated considering the expression of histone deacetylase 6, employing a competitive ELISA, and the modulation of two key miRNAs (miR-153-3p and miR-195-5p), through the miRNeasy Serum/Plasma Mini Kit. ApoE ε4 subjects showed a reduction in plasma AOC and an increase in the Nrf2 blocker, miR-153-3p, contributing to an enhancement of the erythrocyte concentration of Aβ. Physical exercise increased plasma AOC and reduced the amount of Aβ and its precursor, involving a reduced miR-153-3p expression and a miR-195-5p enhancement. Our data highlight the impact of the ApoE genotype on the amyloidogenic pathway and the proteasome system, suggesting the positive impact of physical exercise, also through epigenetic mechanisms.
Highlights
Apolipoprotein E (ApoE) belongs to the family of apolipoproteins, i.e., proteins involved in the lipoprotein assembly, lipid transport, and metabolism by mediating interactions with receptors, enzymes, and lipid transport proteins [1]
The whole cohort of healthy volunteers (8) was divided into ApoE ε4 carriers and ApoE non-ε4 carriers, and based on the results of the Borg score (Section 2.3), the subjects were classified into non-active (NA) and active (A)
The main results of the paper are as follows (Figure 8): (i) plasma antioxidant capability (AOC) was significantly reduced in ApoE ε4 subjects; (ii) the concentration of Aβ, the proteasomerelated Kelch-like ECH-associated protein 1 (Keap1), histone deacetylase 6 (HDAC6), and the nuclear factor erythroid 2-related factor 2 (Nrf2) blocker, miR-153-3p, was augmented in ε4 carriers compared to non-ε4 carriers; (iii) physical exercise was associated with increased plasma AOC and a reduced amount of Aβ and of its precursor amyloid precursor protein (APP); and (iv) physical exercise-induced effects involved a reduced expression of Keap1, HDAC6, and the Nrf2 blocker, miR-153-3p, together with an enhancement of miR-195-5p
Summary
Apolipoprotein E (ApoE) belongs to the family of apolipoproteins, i.e., proteins involved in the lipoprotein assembly, lipid transport, and metabolism by mediating interactions with receptors, enzymes, and lipid transport proteins [1]. The ApoE is mainly associated with chylomicron, very lowdensity lipoprotein (VLDL), and high-density lipoprotein (HDL) [2], delivering lipids through blood, cerebrospinal fluid, and lymph [3]. Each isoform differs from the others for the presence of a cysteine (C) or arginine (R) in positions 112 and 158 of the amino acid sequence of the protein. These dissimilarities in the primary sequence lead to alterations in the structure and function of the ApoE isoforms [5]
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