Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain

Simpson, Julie E.; Ince, Paul G.; Haynes, Lloyd J.; Theaker, R.; Gelsthorpe, Catherine; Baxter, Lynne; Forster, G.; Lace, G; Shaw, Pamela J.; Matthews, Fiona E.; Savva, George M.; Brayne, Carol; Wharton, Stephen B.

doi:10.1111/j.1365-2990.2009.01030.x

Cited by 93 publications

(93 citation statements)

References 53 publications

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“…End joining activity and protein levels of DNAPKcs are reduced in the midfrontal cortex of patients with AD (4). Similarly, a decrease of DNA-PKcs expression, although not significant, was observed in neurons and astrocytes of temporal cortices of AD cases with increasing Braak stages (42). Taken together, these results enable us to hypothesize that during AD pathology continuous accumulation of A␤ and ROS production would impair DNA-PK activity contributing to neurodegeneration through the inhibition of DNA-PK-mediated DSB repair pathway.…”

Section: Discussionmentioning

confidence: 60%

“…The amount of end joining activity correlates with the expression of DNA-PKcs and is dependent on DNA-PK catalytic activity (4). In addition, immunohistochemical analysis of AD temporal cortex showed a decrease, although not significant, of DNA-PKcs expression both in neurons and astrocytes with increasing Braak stages (42). Overall, these findings suggest that repair of DNA DSBs may be deficient in AD, although the molecular candidate causing the NHEJ impairment has yet to be identified.…”

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confidence: 60%

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Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Cardinale

Racaniello

Saladini

et al. 2012

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 60%

mentioning

confidence: 60%

Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Cardinale

Racaniello

Saladini

et al. 2012

Journal of Biological Chemistry

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“…The level of H2AX in astrocytes and neurons was found to significantly decrease with the age of participants (Simpson et al, 2010). Meanwhile, the incidence of endogenous gamma-H2AX foci was increased with age (Sedelnikova et al, 2008).…”

Section: Phosphorylationmentioning

confidence: 82%

“…DNA-PK is required for the NHEJ pathway of DNA repair, whereas, 8-OHdG indicates DNA lesion caused by oxidative damage. Simpson and his colleagues found that the localization of H2AX and DNA-PK demonstrated a good correlation, whereas 8-OHdG localization expression demonstrated a weak correlation with DNA-PK and no significant correlation with H2AX (Simpson et al, 2010). This indicates that H2AX preferentially detects DSBs and is involved in NHEJ repair.…”

Section: Phosphorylationmentioning

confidence: 96%

Involvement of Histone PTMs in DNA Repair Processes in Relation to Age-Associated Neurodegenerative Disease

Wang¹,

Pi²,

Zhan³

et al. 2011

DNA Repair and Human Health

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“…Analyzing transgenic mouse models and neuronal cell cultures, Aβ has been found to accumulate in mitochondria, resulting in elevated hydrogen peroxide production and decreased cytochrome-c oxidase activity, leading to mitochondrial oxidative damage, mitochondrial dysfunction and reduced energy metabolism [176], and cell death. Importantly, it is well established that in return oxidative stress itself increases the generation of Aβ [177][178][179][180], emphasizing oxidative stress to be an important factor in the pathogenesis of AD.…”

Section: Increased Oxidative Stress and Mitochondrial Dysfunctionmentioning

confidence: 99%

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

Grimm¹,

Hartmann²

2011

J Addict Res Ther

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Alzheimer's disease (AD) is the most common form of dementia in the elderly and is characterized in patients by an inexorably progression, causing problems with memory, thinking and behaviour. Currently 25 million people worldwide are estimated to be affected by AD with the highest number in North America, Latin America, Western Europe, China and the western pacific [1]. Epidemiological studies predict that the incidence of AD will increase due to increasing life expectancy to 42.3 million in 2020 and 81.1 million in 2040 [1,2], emphasizing AD as a major public health concern.The two main histopathological hallmarks of AD are extracellular amyloid plaques and intracellular neurofibrillary tangles in vulnerable brain regions like hippocampus and cortex [3]. The amyloid plaques, also called senile plaques, are mainly composed of amyloid-beta peptides (Aβ), most of which are 38 to 43 amino acids long [4]. Aβ peptides are generated by sequential processing of the amyloid precursor protein (APP), a large type-I transmembrane protein [5] that belongs to an evolutionary conserved protein family including beside APP, the APP-like protein 1 (APLP1) and 2 (APLP2) in mammals [6,7] with the Aβ domain to be unique to APP [8]. The second characteristic pathological hallmark of AD, the intracellular neurofibrillary tangles, consist of an abnormally phosphorylated form of the microtubule-associated protein tau [9]. In contrast to amyloid plaques, which accumulate extracellularly in the brains of AD affected individuals and have been long believed to cause neuronal damage and cell death, neurofibrillary tangles are found inside neurons and their branching points like axons and dendrites [10,11]. Proteolytic Processing of APP Amyloidogenic APP processingProteolytic processing of APP leading to Aβ peptides is a ubiquitous cellular process involving β-and γ-secretase activity (Figure 1). The first step in Aβ production is APP cleavage by β-secretase, generating the N-terminus of Aβ. BACE 1 (β-site APP cleaving enzyme, also called Asp2 or memapsin2) was identified as the major β-secretase, a membrane-bound protease that belongs to the pepsin family of aspartyl proteases [12][13][14]. Aβ generation is abolished in cultures of BACE1-deficient embryonic cortical neurons [15] and in BACE1 knock-out mice [16,17]. Whereas Luo and Roberds et al. [16,17] reported a normal phenotype of BACE1-deficient mice, more recent studies found severe phenotypic abnormalities in BACE1 knock-out mice [18], challenging BACE1 as safe drug target for AD. Furthermore, additional BACE1 substrates have been reported, suggesting a variety of BACE1 physiological functions. Identified substrates include proteins with important neuronal function, like the β2-subunit of the voltage-gated sodium channel (Navβ2) [19,20], important for normal action potential regulation and neuronal excitability, and neuregulin-1 [21,22], as ligand for members of the ErbB family of receptor-tyrosine kinases, involved in synapse formation, myelination of central and peripheral axon...

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Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain

Cited by 93 publications

References 53 publications

Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Sublethal Doses of β-Amyloid Peptide Abrogate DNA-dependent Protein Kinase Activity

Involvement of Histone PTMs in DNA Repair Processes in Relation to Age-Associated Neurodegenerative Disease

Recent Understanding of the Molecular Mechanisms of Alzheimer?s Disease

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