**3. Role of oxidative stress in pathogenesis of Alzheimer's disease (AD)**

Alzheimer's disease (AD) is the most common neurodegenerative disease, characterised by gradual declines in memory, behaviour, and functionality that severely limit day-to-day activities [49]. The pathophysiology of Alzheimer's disease is primarily linked to the formation of extracellular amyloid beta (Aβ) plaques and intracellular tau neurofibrillary tangles (NFT) [50]. Plaques in the endoplasmic reticulum (ER) can deplete calcium ions (Ca2+) storage, resulting in cytosolic Ca2+ overload. Endogenous GSH levels are reduced in response to an increase in cytosolic Ca2+, and ROS will accumulate within the cells [51]. ROS-induced ROS overproduction is believed to play a critical role in the aggregation and secretion of Aβ in AD, and oxidative stress is emerging as a significant factor in the pathogenesis of AD [52]. Mitochondrial dysfunction can result in increased production of reactive oxygen species (ROS), decreased ATP production, altered Ca2+ homeostasis, and excitotoxicity. All these alterations may be implicated in the development of AD [53].

Overactivation of N-methyl-D-aspartate-type glutamate receptors (NMDARs) can cause severe oxidative stress in Alzheimer's patients. NMDAR activation has been showed to trigger excessive Ca2+ influx by increasing cell permeability and resulting in the production of neurotoxic levels of reactive oxygen and nitrogen species (RNS) [54, 55]. JNK/stress-activated protein kinase pathways can be mediated by reactive oxygen species (ROS). The hyperphosphorylation of tau proteins and Aβ-induced cell death have both been linked to the activation of these cascades [56]. Furthermore, Aβ proteins can directly cause formation of free radicals by inducing NADPH oxidase [57]. The activation of p38 mitogen activated protein kinase (p38 MAPK) by Aβ-induced ROS overproduction modifies cellular signalling pathways and initiates tau hyperphosphorylation. Intracellular NFT formation may be caused by an abnormal aggregation of hyperphosphorylated tau proteins [58, 59]. Consequently, Aβ has been shown to play a key role in the induction of cellular apoptosis [60]. Aβ may boost the activity of calcineurin, which then activates the Bcl-2-associated death promoter, causing mitochondrial cytochrome c release [61]. Aβ can also interact directly with caspases, resulting in neuron apoptosis [61].

Environmental stress, ageing, inflammation, and certain dietary factors (e.g., redox-active metals) may all trigger an increase in Aβ output by inducing additional oxidative stress [62]. Oxidative stress is more common in the elderly, which helps to explain why older people are more susceptible to Alzheimer's disease [62]. Increased expression of cytokines, ROS levels, and cellular toxicity are all caused by inflammation, which accelerates the development of Alzheimer's disease [63]. Aβ deposition results in microglial activation [64]. It's becoming clear that sustained activation of microglia results in the release of pro-inflammatory cytokines, triggering a proinflammatory cascade and leading to neuronal loss and damage [65]. Environmental factors such as toxins, chemicals, and radiation may cause oxidative stress [66]. The production of reactive oxygen species (ROS) increases, where there are excess iron deposits [66]. Aβ itself can interact with metal ions to generate free radicals, therefore methionine 35 plays an important role in these reactions [67]. Cu2+/Zn2+-bound Aβ has been showed to have a structure identical to superoxide dismutase (SOD),

*Reactive Oxygen Species in Neurodegenerative Diseases: Implications in Pathogenesis… DOI: http://dx.doi.org/10.5772/intechopen.99976*

suggesting that it could have antioxidant properties [68]. As a result, Cu2+ and Zn2+ supplementation has been considered as a novel strategy to reduce Aβ-induced ROS generation and metal catalysed Aβ deposition [68].

Drugs for Alzheimer's disease are aimed at lowering Aβ oligomers and phosphorylated tau levels, lowering oxidative stress, and regulating epigenetic changes [69]. The majority of Alzheimer's disease therapies depend on compounds with neuroprotective, anti-inflammatory, and antioxidant properties [70]. Medications that target ROS-mediated cascades like JNK and NF-B (e.g., tocopherol, resveratrol, and rutin) have demonstrated some promising results *in vitro* and *in vivo* [49]. When using antioxidants, significant factors including reaction kinetics and bioavailability (permeability, retention in the targeted region, distribution, and transport) must be taken into account [70]. Several ROS-related neuroprotective therapeutic techniques have shown great promise in the treatment of Alzheimer's disease. The antioxidant response element (ARE) pathway regulated by nuclear factor erythroid 2-related factor 2 (Nrf2) is known to be an important conditioned response against oxidative stress [71]. The binding of Nrf2 to ARE activates the expression of several antioxidant genes in a synchronised manner that can work together for oxidative detoxification. Weakened Nrf2-ARE pathways were observed in the brains of transgenic mice with AD symptoms, while the enhancement of Nrf2-ARE cascades using adenoviral Nrf2 gene transfer has shown protective effects against the toxicity of Aβ deposition [71]. As a result, transcriptional modulation of endogenous antioxidants could hold great promise in the treatment of Alzheimer's disease symptoms [71].
