**4.1 Amyloid-β and oxidative stress**

Aβ binds and reduces Fe3+ and Cu2+ in presence of endogenous reducing agents to generate H2O2 further producing other partially ROS [86, 87]. Studies have revealed the role of metal ions such as Fe, Cu and Zn in inducing Aβ aggregation

**199**

Mn-SOD [93].

**4.3 Protective mechanisms from ROS**

*Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer's Disease*

downstream consequences of increase in Aβ42 concentration [91].

Excessive free radical production as a result of oxidative stress at cellular levels causes protein oxidation and lipid peroxidation [91]. Lipid peroxidation leads to break down of unsaturated fatty acids among other components of membrane phospholipids, leading to accumulation of isoprostanes, acrolein, thiobarbituratereactive substances, etc. [84, 92]. Glutamate receptors overstimulation can trigger downstream cell death cascades through increased calcium influx and generation of nitric oxide species [48]. 8-hydroxy-2′-deoxyguanosine (OHDG) is one of the oxidative markers for DNA, found in PD patients [36]. These products impair glucose transport and glutamate uptake, hence contributing to cell apoptosis. ROS cause imbalance in metal and ion homeostasis, for example Ca2+, which can trigger imbalance in downstream signaling cascades. Oxidative damage can lead to hydroxylation of nucleic acids and carbonylation of proteins. Carbonyls are markers of protein oxidation and have been found concentrated in frontal brain regions of AD patients [92]. Free radicals generated as result of amyloid oligomerization or aggregation can directly mediate mitochondrial damage which triggers neuronal death through downstream pathways, one of them being cytochrome C reduction [48]. OS in PD cases may be a result of deregulation of dopamine-iron redox pathway, since αS can alter expression of enzymes indirectly regulating dopamine synthesis [84]. αS is also known to directly interact with metal ions causing protein aggregation. ALS is mainly characterized by loss of motor neurons, which combined with SOD mutations diminishing its free radical scavenging abilities can exacerbate the impacts to oxidative injury [84]. Oxidative markers localized in plaques and NFTs are toxic products such as 3-nitrotyrosine, HNE, pyrraline and pentosidine, while metal enriched protein carbonyls including ferritin, catalyst, Cu/Zn-SOD and

Chaperones can bind ROS generated as by-product of amyloids and thus prevent triggering breakdown of homeostasis. α2-Macroglobulin can directly bind Aβ and potentially act as a chaperone in addition to its zinc-binding capabilities which can help mitigate redox activity of Aβ [94]. Zn2+ is redox-inert and may be helpful in mitigating metal mediated Aβ redox activity. ApoE can mediate Aβ clearance as a chaperone depending on specific isoform interactions; ε4 may potentially increase

and oligomerization [88–90]. Brain regions rich in Aβ(1–42) show increased oxidative stress, possibly mediated through redox interactions with the only methionine (Met35) present in peptide sequence [91]. Amyloids oligomers can also trigger ROS generation [2]. The three histidine residues-His6, His13 and His14, facilitate Aβ coordination with transition metal ions. These residues get protonated in acidic environment and may increasingly contribute to aggregation at low pH. Cu2+ interacts with Aβ and oxidizes sulfur of Met35 to activate formation of disulfide bonds leading to dimerization and other oligomeric formations. Soluble oxidized aggregates avoid clearance causing enrichment of brain regions with these agglomerates. Aβ peptides can successfully recruit ions of metals like Fe, Cu and Zn through sulfide group of Met35 and a chelating domain which involves Asp1 and all three histidines, in a bid to induce redox complexes capable of bringing about oxidative insults [7]. Dityrosine cross-linked Aβ dimers along with nitrotyrosine cross-linked proteins are also associated with oxidative stress [92]. Cell death from oxidative stress is a cumulative result of alteration in proteostasis, protein phosphorylation and glucose metabolism as

*DOI: http://dx.doi.org/10.5772/intechopen.84238*

**4.2 Pathophysiology of ROS**

*Neuroprotective Function of Non-Proteolytic Amyloid-β Chaperones in Alzheimer's Disease DOI: http://dx.doi.org/10.5772/intechopen.84238*

and oligomerization [88–90]. Brain regions rich in Aβ(1–42) show increased oxidative stress, possibly mediated through redox interactions with the only methionine (Met35) present in peptide sequence [91]. Amyloids oligomers can also trigger ROS generation [2]. The three histidine residues-His6, His13 and His14, facilitate Aβ coordination with transition metal ions. These residues get protonated in acidic environment and may increasingly contribute to aggregation at low pH. Cu2+ interacts with Aβ and oxidizes sulfur of Met35 to activate formation of disulfide bonds leading to dimerization and other oligomeric formations. Soluble oxidized aggregates avoid clearance causing enrichment of brain regions with these agglomerates. Aβ peptides can successfully recruit ions of metals like Fe, Cu and Zn through sulfide group of Met35 and a chelating domain which involves Asp1 and all three histidines, in a bid to induce redox complexes capable of bringing about oxidative insults [7]. Dityrosine cross-linked Aβ dimers along with nitrotyrosine cross-linked proteins are also associated with oxidative stress [92]. Cell death from oxidative stress is a cumulative result of alteration in proteostasis, protein phosphorylation and glucose metabolism as downstream consequences of increase in Aβ42 concentration [91].
