1. Chapter 18 Dietary Phytochemicals in Neurodegenerative Disease
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FIGURE 18.1 Diagram illustrating how Aβ peptides are released from APP via successive β- and γ-secretase cleavages. APP is shown as a transmembrane protein in the phospholipid bilayer (phospholipid headgroups are shown as filled circles; acyl chains are depicted as “tails” associated with each headgroup). The cleavage sites are shown in the representation of APP: β-secretase cleaves between residues 671 and 672, and γ-secretase cleaves between residues 711 and 712, yielding Aβ140, or , yielding Aβ142. PS, presenilin. Adapted from J.-C. Rochet, Novel therapeutic strategies for the treatment of protein-misfolding diseases, Expert Rev. Mol. Med. 9 (2007) PART | B Dietary Bioactive Compounds for Health
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FIGURE 18.2 Model illustrating mechanisms of glial activation and neurotoxicity. Neurotoxic insults result in neuronal death or damage. Factors released from dying or damaged neurons (e.g., protein aggregates) can activate glial cells and result in the production of proinflammatory molecules including ROS, RNS, and cytokines. These agents can in turn damage neighboring neurons. Thus, a vicious cycle occurs between damaged neurons and activated microglia, resulting in
progressive neurotoxicity. Adapted from M.L. Block, L. Zecca, J.S. Hong, Microglia-mediated neurotoxicity: uncovering the molecular mechanisms, Nat. Rev. Neurosci. 8 (1) (2007) 5769.
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FIGURE 18.3 Model illustrating mechanisms of aSyn aggregation and neurotoxicity. aSyn is a natively unfolded protein that undergoes self-assembly under pathological conditions. aSyn aggregation involves the formation of intermediate species named protofibrils that undergo further assembly into larger amyloid-like fibrils. These fibrillar species are the main constituents of pathological inclusions named Lewy bodies. aSyn aggregation leads to membrane disruption, impairment of lysosomal autophagy, and UPS inhibition.
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FIGURE 18.4 Model illustrating the mechanism of rotenone-mediated oxidative stress. Rotenone diffuses freely through the cell membrane and outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM), where it inhibits complex I of the electron transport chain. A decrease in complex I activity leads to electron leakage, a buildup of
ROS (e.g., superoxide, O2 2 ), disruption of oxygen consumption, depletion of ATP, and the release of cytochrome C into the cytosol.
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FIGURE 18.5 Schematic illustrating the mechanism of PQ-mediated oxidative stress. A redox cycling reaction involving
the interconversion of monocationic and dicationic forms of PQ results in the production of ROS.
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FIGURE 18.6 Classification of polyphenols, showing generic chemical structures of ANCs and isoflavones.
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FIGURE 18.7 Chemical structures of different classes of polyphenols. The structures are of a generic flavonoid (A), showing the A, B, and C rings; a generic phenolic acid (B); the stilbene resveratrol (C); and the lignan enterodiol (D).
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FIGURE 18.8 Schematic illustrating the classic mechanism of Nrf2 activation. Under normal conditions, Keap1 sequesters Nrf2 in the cytoplasm and regulates its ubiquitination by cullin-3 and subsequent degradation by the UPS. Under conditions of oxidative stress, the oxidation of cysteine residues on Keap1 results in its conformational change and the release of Nrf2. Nrf2 translocates to the nucleus, where it heterodimerizes with Maf, binds to the ARE, and activates the transcription
of genes encoding antioxidant enzymes.
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FIGURE 18.9 Model illustrating polyphenol-mediated antioxidant responses. Nrf2 levels increase in astrocytes as a result of ROS- or polyphenol-induced dissociation of Nrf2 from its repressor protein Keap1 (“K”), or as a result of polyphenol-mediated UPS inhibition. A build-up of astrocytic Nrf2 leads to an increase in the expression of genes involved in the cellular antioxidant response, including heme oxygenase 1 (HO-1), NQO1, and GCL, an enzyme involved in GSH synthesis. GSH subunits produced as a result of GSH metabolism are released from astrocytes and imported into neurons, where they are reassembled into GSH. Polyphenols can also induce an antioxidant response by ameliorating mitochondrial dysfunction
(shown here in neurons exposed to rotenone) by (i) activating PGC-1α, a transcriptional co-activator that induces mitochondrial biogenesis and the expression of ROS-detoxifying enzymes; and (ii) displacing rotenone from complex I of the electron transport chain.
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