Intraneuronal amyloid β accumulation and oxidative damage to nucleic acids in Alzheimer disease

Department of Neuropsychiatry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan.
Neurobiology of Disease (Impact Factor: 5.08). 03/2010; 37(3):731-737. DOI: 10.1016/j.nbd.2009.12.012


In an analysis of amyloid pathology in Alzheimer disease, we used an in situ approach to identify amyloid-β (Aβ) accumulation and oxidative damage to nucleic acids in postmortem brain tissue of the hippocampal formation from subjects with Alzheimer disease. When carboxyl-terminal-specific antibodies directed against Aβ40 and Aβ42 were used for immunocytochemical analyses, Aβ42 was especially apparent within the neuronal cytoplasm, at sites not detected by the antibody specific to Aβ-oligomer. In comparison to the Aβ42-positive neurons, neurons bearing oxidative damage to nucleic acids were more widely distributed in the hippocampus. Comparative density measurements of the immunoreactivity revealed that levels of intraneuronal Aβ42 were inversely correlated with levels of intraneuronal 8-hydroxyguanosine, an oxidized nucleoside (r=− 0.61, p

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    • "However, neuronal oxidative damage is more pronounced in AD patients with less Aβ deposition or with a shorter disease duration [95] . There is an inverse relationship between the degree of oxidative damage of nucleic acids in neurons and the amounts of intraneuronal Aβ 42 in the hippocampus of the AD brain [96] . How can this contradiction be interpreted? "
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    ABSTRACT: Oxidative stress plays a significant role in the pathogenesis of Alzheimer's disease (AD), a devastating disease of the elderly. The brain is more vulnerable than other organs to oxidative stress, and most of the components of neurons (lipids, proteins, and nucleic acids) can be oxidized in AD due to mitochondrial dysfunction, increased metal levels, inflammation, and β-amyloid (Aβ) peptides. Oxidative stress participates in the development of AD by promoting Aβ deposition, tau hyperphosphorylation, and the subsequent loss of synapses and neurons. The relationship between oxidative stress and AD suggests that oxidative stress is an essential part of the pathological process, and antioxidants may be useful for AD treatment.
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    • "Furthermore, Aβ peptides capture metal ions such as Zn, Fe, and Cu, potentially reducing oxidative stress to neurons [25]. This is consistent with the notion that increased oxidative damage is an early feature in AD development [26-29] and with findings that subsequent increases in Aβ accumulation correlates with the decrease in oxidative stress [27,30]. Similarly, physiological levels of Aβ peptides in plasma and cerebrospinal fluid (CSF) are reported to protect circulating lipoproteins from oxidation [31]. "
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    ABSTRACT: For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic.
    Full-text · Article · Sep 2013
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    • "Alternatively, the augmentation of Abeta production by oxidative stress may be a compensatory reaction to oxidative stress. It was found that neuronal oxidative damage was more pronounced in AD subjects with lesser amounts of Abeta deposition or in AD subjects with a shorter disease duration [61, 62], and there was an inverse relationship between the levels of neuronal oxidative damage to nucleic acids and the amounts of intraneuronal Abeta42 in the hippocampus and the subiculum of AD brains [63]. These unexpected observations have led to the hypothesis that Abeta may potentially play a protective role against neuronal oxidative stress [64]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common neurodegenerative disease that causes dementia in the elderly. Patients with AD suffer a gradual deterioration of memory and other cognitive functions, which eventually leads to a complete incapacity and death. A complicated array of molecular events has been implicated in the pathogenesis of AD. The major pathological characteristics of AD brains are the presence of senile plaques, neurofibrillary tangles, and neuronal loss. Growing evidence has demonstrated that oxidative stress is an important factor contributing to the initiation and progression of AD. However, the mechanisms that lead to the disruption of redox balance and the sources of free radicals remain elusive. The excessive reactive oxygen species may be generated from mechanisms such as mitochondria dysfunction and/or aberrant accumulation of transition metals, while the abnormal accumulation of Abeta and tau proteins appears to promote the redox imbalance. The resulted oxidative stress has been implicated in Abeta- or tau-induced neurotoxicity. In addition, evidence has suggested that oxidative stress may augment the production and aggregation of Abeta and facilitate the phosphorylation and polymerization of tau, thus forming a vicious cycle that promotes the initiation and progression of AD.
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