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Tamagno, E. Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/16624 (accessed on 14 October 2024).
Tamagno E. Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/16624. Accessed October 14, 2024.
Tamagno, Elena. "Oxidative Stress and Beta Amyloid in Alzheimer’s Disease" Encyclopedia, https://encyclopedia.pub/entry/16624 (accessed October 14, 2024).
Tamagno, E. (2021, December 01). Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. In Encyclopedia. https://encyclopedia.pub/entry/16624
Tamagno, Elena. "Oxidative Stress and Beta Amyloid in Alzheimer’s Disease." Encyclopedia. Web. 01 December, 2021.
Oxidative Stress and Beta Amyloid in Alzheimer’s Disease
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This entry is adapted from the peer-reviewed paper 10.3390/antiox10091479

The pathogenesis of Alzheimer's disease (AD) involves beta amyloid accumulation known to induce synaptic dysfunction and neurodegenration. The brain's vulnerability to oxidative stress (OS) is considered a crucial detrimental factor in AD. OS and beta amyloid are linked each other because beta amyloid induces OS and, in turn, OS induces beta amyloid accumulation. Evidence indicates that a gradual oxidative damage  accumulation precedes and results in the appearance of pathological AD symptoms. Moreover, OS plays a crucial role in the pathogenesis of many risk factors for AD.

Alzheimer’s disease oxidative stress

1. Introduction

Alzheimer’s disease (AD) is considered the leading cause of dementia and is becoming one of the most expensive and deadly diseases of our time [1]. Thus, it is estimated that 50 million people worldwide endure dementia, and this number is set to rise to 152 million in 2050 [2][3]. Moreover, Alzheimer’s patients need specialized and expensive care, the annual cost of treatment worldwide is around a trillion US dollars, and it is predicted that this cost will significantly increase by 2030 [4].
The pathophysiology of the disease is complex and multifactorial and certainly not entirely known [3]. There are two markers of the disease. One is β amyloid (Aβ), which accumulates abnormally in AD brain tissues and forms extracellular plaques known to induce synaptic alterations and neurodegeneration [5][6]. The other is Tau protein, which forms intracellular neurofibrillary tangles that are also responsible for neurodegeneration [7][8].
AD is traditionally divided into two forms: early and late onset forms. The early onset form is closely associated with mutations on three genes: the genes that encode for the amyloid precursor (APP) and for presenilin 1 and presenilin 2, which represent the catalytic core of γ-secretase, a key enzyme for the production of Aβ [9]. The late onset form is caused by complex interactions between genetic and environmental factors [10][11]. APOE is the gene that was first associated with the development of the late form [12] compared to other predisposing genes that have been described. These include genes involved in neuroinflammation (such as TREM2, TYROBP, and CD33) [13][14][15], memory (CR1, PICALM, and BIN1) [16][17][18], and lipid metabolism (ABCA7 and CLU) [19][20].
Thus, although there are numerous factors associated with the development of the disease, Aβ represents one that is the most closely related to its pathogenesis. Aβ is composed of polypeptides of various lengths, and most of those found in the plaques are 40 and 42 amino acids long [6]. Aβ 40 is the most abundant form and accounts for 90% of the amyloid present in the plaques; however, the longer form (Aβ 42) is predominant in the initial phases and aggregates faster than Aβ 40 [21]. Aβ is produced from the amyloid precursor protein (APP). APP is an integral membrane protein with a large, extracellular N-terminus and a shorter, cytoplasmic C-terminus [22][23]. The amyloidogenic processing of APP involves two sequential cleavages operated by the β-secretases and γ-secretases. The β-secretase (BACE1) cleaves APP, generating an extracellular soluble fragment called sβAPP and an intracellular C-terminal end termed C99 [24]. C99 is further cleaved, within the membrane, by the γ-secretase [25]. The γ-cleavage produces Aβ fragments of different lengths, and these are predominantly Aβ 40 and Aβ 42 [25].

2. Aβ vs. Oxidative stress

There are numerous mechanisms described in the literature by which beta amyloid (Aβ) mediates oxidative damage (Figure 1).
Antioxidants 10 01479 g001 550
Figure 1. Diagram sketching mechanisms by which Aβ induces oxidative stress.

2.1. Mitochondria

Aβ interferes with the normal mitochondrial activity, causing dysfunction that results in oxidative stress [26]. Thus, neurons are cells that require high energy levels to perform numerous functions, such as the generation of action potentials, nerve transmission, and axonal transport [27].
The alteration of oxidative phosphorylation (OXPHOS) involves a reduction in the efficiency to transfer electrons, which in turn results in an increase in ROS production predominantly at level of complex I and complex III. These ROSs generated at the chain level unfold their damaging action mainly on mitochondrial macromolecules [28]. The peptide Aβ not only promotes the generation of ROS at the level of the mitochondria, but inhibits, at the same time, ROS removal. In fact, it has been shown that Aβ is able to inhibit mitochondrial superoxide dismutase (MnSOD), the enzyme most involved in the detoxification of the anion superoxide and protection from peroxidative damage [29][30]. Aβ is also capable of binding and inhibiting mitochondrial alcohol dehydrogenase known as ABAD (Aβ binding alcoholdehydrogenase). ABAD has a protective role, being responsible for the detoxification from aldehydes such as 4-hydroxinonenal. The interaction between the Aβ peptide and ABAD compromises the detoxification process for which the enzyme is responsible for, causing lipid peroxidation, ROS generation, and mitochondrial dysfunction [31].
Furthermore, from the direct impact of Aβ on mitochondria, some authors also demonstrated that mitochondrial DNA is altered in elderly and AD patients [32]. Various factors can influence mitochondrial activity, contributing to AD progression. [33]. In brain tissue of AD cases, there is a downregulation of genes in mitochondrial complex I of the OXPHOS [34], and OS is implicated in mtDNA damage [35].

2.2. Transition Metals

Another mechanism found dysregulated in AD is the homeostasis of metals such as iron (Fe), copper (Cu), and zinc (Zn). The blood–brain barrier tightly regulates the concentration of these metals, but their levels significantly increased in AD patients [36][37]. Studies have shown that Aβ plaques contain traces of these metals [38], and Aβ can reduce Fe (III) or Cu (II) to induce hydrogen peroxide (H2O2) production, contributing to OS in AD [39]. Moreover, some studies suggested that these metals can increase Aβ polymerization; thus, neuroblastoma cells treated with Fe3+ caused an increase in BACE1 activity that, in turn, promotes Aβ production [40]. Moreover, zinc is also abundant in amyloid plaques, suggesting its role in AD. Zinc interacts with Aβ protein, and this interaction can be prevented by chelators [41][42]. ZnAβ oligomers mediate stronger toxicity than amyloid-beta derived diffusible ligands (ADDLs) by cell viability assays [43]. The ex vivo study showed that ZnAβ oligomers inhibited hippocampal LTP in a transgenic mouse model also through the production of ROS [44].

2.3. Heme

Another important iron containing molecule that has been implicated in the pathogenesis of AD is heme. Heme is an essential molecule in various physiological and pathological mechanisms [45]. It has been suggested that AD patients had lower hemoglobin levels and smaller cell volume with respect to normal aging controls [46]. Complexes II, III, and IV of the electron transport chain require heme to assembly cytochromes needed to function [47]. Perturbation in heme metabolism can cause oxidative stress and cell death [48]. Sankar and collaborators found that heme can mitigate the Aβ 42-mediated neuroinflammation activated by astrocytes [49]. Heme can also bind to Aβ, and this complex is known to have peroxidase activity able to oxidize serotonin and DOPA and providing an intriguing link between heme and oxidative stress in AD [50]. Thus, heme deficiency is followed by formation of APP dimers and loss of complex IV of the electron transport chain, and this event causes OS [51]. This finding suggested that iron accumulation observed in AD could be strictly linked to heme deficiency [51].

2.4. Neuroinflammation

Another crucial mechanism through which the presence of Aβ induced oxidative stress is neuroinflammation [52]. Neuroinflammation is considered as an immunological response characterized by the activation of glial cells and the production of inflammatory mediators [53]. Numerous studies revealed a strong correlation between neuroinflammation and AD pathology [54][55][56]; thus, inflammatory cytokines have been reported to increase in the progression of mild cognitive impairment to overt AD [57]. A microarray study of Cribbs and collaborators performed on young, aged, and AD cases demonstrated an upregulation of the innate immune response in aging brains and a slight increase in related genes [58], suggesting that inflammation has a role in the preclinical stages of AD. In this context, microglia play a leading role in neuroinflammation [53]. Aβ can bind different microglial receptors, resulting in the production not only of inflammatory cytokines and chemokines [58] but also of a large amount of oxygen free radicals (•OH and O₂•) [59], nitric oxide (•NO) [60], and tumour necrosis factor (TNF) α [61]. The NLR family pyrin domain containing 3 (NLRP3) inflammasome is a recently found cytoplasmic protein complex involved in neuroinflammation and innate immune response [62]. Recent studies demonstrated that Aβ induce NLRP3 activation in microglia and astrocytes. This event results in the production of caspase 1 and induces the release of cytokines such as IL1β and IL-18, resulting in irreversible damage. On the other hand, the inhibition of NLRP3 inflammasome inhibits Aβ deposition and had a neuroprotective effect in a transgenic AD mouse model [63][64][65][66]. Thus, all these findings suggest that Aβ is a crucial factor in AD associated inflammation and oxidative stress.

2.5. NF-kB Pathway

The NF-kB family also has an important role in modulating oxidative stress. Thus, evidence from in vitro studies showed increased oxidative stress-mediated by NF-kB in response to neurons exposed to Aβ; this increased oxidative stress resulted in the accumulation of lipid peroxides and neurodegeneration [67]. Moreover, many studies confirm that Aβ peptides stimulate NF-kB gene expression and its nuclear translocation [68][69][70].
 

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Elena Tamagno
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