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Oxidant/Antioxidant Imbalance and the Risk of Alzheimer's Disease

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia characterized by progressive loss of memory and other cognitive functions among older people. Senile plaques and neurofibrillary tangles are the most hallmarks lesions in the brain of AD in addition to neurons loss. Accumulating evidence has shown that oxidative stress–induced damage may play an important role in the initiation and progression of AD pathogenesis. Redox impairment occurs when there is an imbalance between the production and quenching of free radicals from oxygen species. These reactive oxygen species augment the formation and aggregation of amyloid-β and tau protein hyperphosphorylation and vice versa. Currently, there is no available treatments can modify the disease. However, wide varieties of antioxidants show promise to delay or prevent the symptoms of AD and may help in treating the disease. In this review, the role of oxidative stress in AD pathogenesis and the common used antioxidant therapies for AD will summarize.

No MeSH data available.


Related in: MedlinePlus

Amyloid hypothesis. During AD development, amyloid precursor protein is cleavage to produce β amyloid peptide that aggregates and accumulates to form amyloid-β plaques. This plaques cause neurotoxicity or microglia activation, which in turn microglia release ROS and many pro-inflammatory cytokines such as NO, PGE2, IL-1, IL-6, and TNF-α that accelerate cholinergic neuron damage. These pro-inflammatory cytokines subsequently activate astrocytes that also produce more cytokines to amplify the inflammatory signals and result in neuroinflammation and neurodegeneration.
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Figure 1: Amyloid hypothesis. During AD development, amyloid precursor protein is cleavage to produce β amyloid peptide that aggregates and accumulates to form amyloid-β plaques. This plaques cause neurotoxicity or microglia activation, which in turn microglia release ROS and many pro-inflammatory cytokines such as NO, PGE2, IL-1, IL-6, and TNF-α that accelerate cholinergic neuron damage. These pro-inflammatory cytokines subsequently activate astrocytes that also produce more cytokines to amplify the inflammatory signals and result in neuroinflammation and neurodegeneration.

Mentions: Histopathology of post-mortem brains obtained from AD clinically characterized patients provided the first clues to the mechanisms of disease and potential interventions. It led to the description of the disease a century ago by Alois Alzheimer [1], and the identification of the AD hallmark lesions. The histopathological changes include extracellular deposits of amyloid-β (Aβ) forming senile plaques and intracellular neurofibrillary tangles (NFT) formed by accumulation of abnormal hyperphosphorylated filaments of tau in pyramidal neurons. Besides these features, a large body of evidence indicates prominent activation of inflammatory processes and the innate immune response activation. Classic senile plaques are spherical structures consisting of a central core of Aβ fibrous protein that is surrounded by degenerating or dystrophic nerve endings. The Aβ protein contains a 40 or 42 amino acid peptide of Aβ that is derived from proteolytic processing of a larger amyloid precursor protein (APP) molecule via two pathways: the α pathway and the β pathway. APP is degraded by α-secretase to produce a non-amyloidogentic molecules, whereas the sequential enzymatic actions of beta-site APP-cleaving enzyme 1 (BACE-1), a β-secretase, generated small APPβ (sAPPβ) in the extracullar space. sAPPβ is subsequently degraded by γ-secretase, a protein complex contains presenilin 1 at its catalytic core, to release Aβ and APP intracellular C-terminal domain (AICD) [2]. It is believed that the most toxic Aβ40–42 peptides are resulted by the abnormal processing of the APP molecule [3]. However, the produced Aβ is degraded by many enzymes includes, but not limited to, insulin-degrading enzyme (IDE) and neprilysin (NEP). NEP and IDE are reduced in AD [4]. The imbalance between Aβ production and clearance causes Aβ to accumulate in the extracellular space. Aβ1–42 readily forms insoluble clumps and initiates a cascade of events leading to apoptosis and neuronal dysfunction or death. This process called the amyloid hypothesis (Fig. 1).


Oxidant/Antioxidant Imbalance and the Risk of Alzheimer's Disease
Amyloid hypothesis. During AD development, amyloid precursor protein is cleavage to produce β amyloid peptide that aggregates and accumulates to form amyloid-β plaques. This plaques cause neurotoxicity or microglia activation, which in turn microglia release ROS and many pro-inflammatory cytokines such as NO, PGE2, IL-1, IL-6, and TNF-α that accelerate cholinergic neuron damage. These pro-inflammatory cytokines subsequently activate astrocytes that also produce more cytokines to amplify the inflammatory signals and result in neuroinflammation and neurodegeneration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5384363&req=5

Figure 1: Amyloid hypothesis. During AD development, amyloid precursor protein is cleavage to produce β amyloid peptide that aggregates and accumulates to form amyloid-β plaques. This plaques cause neurotoxicity or microglia activation, which in turn microglia release ROS and many pro-inflammatory cytokines such as NO, PGE2, IL-1, IL-6, and TNF-α that accelerate cholinergic neuron damage. These pro-inflammatory cytokines subsequently activate astrocytes that also produce more cytokines to amplify the inflammatory signals and result in neuroinflammation and neurodegeneration.
Mentions: Histopathology of post-mortem brains obtained from AD clinically characterized patients provided the first clues to the mechanisms of disease and potential interventions. It led to the description of the disease a century ago by Alois Alzheimer [1], and the identification of the AD hallmark lesions. The histopathological changes include extracellular deposits of amyloid-β (Aβ) forming senile plaques and intracellular neurofibrillary tangles (NFT) formed by accumulation of abnormal hyperphosphorylated filaments of tau in pyramidal neurons. Besides these features, a large body of evidence indicates prominent activation of inflammatory processes and the innate immune response activation. Classic senile plaques are spherical structures consisting of a central core of Aβ fibrous protein that is surrounded by degenerating or dystrophic nerve endings. The Aβ protein contains a 40 or 42 amino acid peptide of Aβ that is derived from proteolytic processing of a larger amyloid precursor protein (APP) molecule via two pathways: the α pathway and the β pathway. APP is degraded by α-secretase to produce a non-amyloidogentic molecules, whereas the sequential enzymatic actions of beta-site APP-cleaving enzyme 1 (BACE-1), a β-secretase, generated small APPβ (sAPPβ) in the extracullar space. sAPPβ is subsequently degraded by γ-secretase, a protein complex contains presenilin 1 at its catalytic core, to release Aβ and APP intracellular C-terminal domain (AICD) [2]. It is believed that the most toxic Aβ40–42 peptides are resulted by the abnormal processing of the APP molecule [3]. However, the produced Aβ is degraded by many enzymes includes, but not limited to, insulin-degrading enzyme (IDE) and neprilysin (NEP). NEP and IDE are reduced in AD [4]. The imbalance between Aβ production and clearance causes Aβ to accumulate in the extracellular space. Aβ1–42 readily forms insoluble clumps and initiates a cascade of events leading to apoptosis and neuronal dysfunction or death. This process called the amyloid hypothesis (Fig. 1).

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia characterized by progressive loss of memory and other cognitive functions among older people. Senile plaques and neurofibrillary tangles are the most hallmarks lesions in the brain of AD in addition to neurons loss. Accumulating evidence has shown that oxidative stress–induced damage may play an important role in the initiation and progression of AD pathogenesis. Redox impairment occurs when there is an imbalance between the production and quenching of free radicals from oxygen species. These reactive oxygen species augment the formation and aggregation of amyloid-β and tau protein hyperphosphorylation and vice versa. Currently, there is no available treatments can modify the disease. However, wide varieties of antioxidants show promise to delay or prevent the symptoms of AD and may help in treating the disease. In this review, the role of oxidative stress in AD pathogenesis and the common used antioxidant therapies for AD will summarize.

No MeSH data available.


Related in: MedlinePlus