Impact of NMDA receptor activation on DNA damage in PC12 neuron-like cell cultures in the presence of β-amyloid peptides

Wiatrak, Benita; Mieszała, Przemysław; Gąsiorowski, Kazimierz

doi:10.1007/s11033-022-07856-6

Cited by 5 publications

(3 citation statements)

References 51 publications

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“…Links have also been reported between Aβ plaques and DNA damage. Aβ induces oxidative stress, in part by interfering with normal mitochondrial activity 97 , and induces oxidative DNA damage 79 as shown by 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining and histone phosphorylation (γ-H2AX) 98 – 100 . Aβ may also contribute indirectly by inhibiting NHEJ by blocking DNA-dependent protein kinase, thereby promoting oxidative DNA damage 101 .…”

Section: Discussionmentioning

confidence: 99%

Sting and p53 DNA repair pathways are compromised in Alzheimer’s disease

Nelson

2023

Sci Rep

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Alzheimer’s disease (AD) is the most common cause of dementia. A common finding in AD is DNA damage. Double-strand DNA breaks (DSBs) are particularly hazardous to neurons because their post-mitotic state forces neurons to rely on error-prone and potentially mutagenic mechanisms to repair DNA breaks. However, it remains unclear whether DNA damage results from increased DNA damage or failure of DNA repair. Oligomerization of the tumor suppressor protein p53 is an essential part of DSB repair, and p53 phosphorylated on S15 is an indicator of DNA damage. We report that the monomer:dimer ratio of phosphorylated (S15) p53 is increased by 2.86-fold in temporal lobes of AD patients compared to age-matched controls, indicating that p53 oligomerization is compromised in AD. In vitro oxidation of p53 with 100 nM H2O2 produced a similar shift in the monomer:dimer ratio. A COMET test showed a higher level of DNA degradation in AD consistent with double-strand DNA damage or inhibition of repair. Protein carbonylation was also elevated (190% of control), indicating elevated oxidative stress in AD patients. Levels of the DNA repair support protein 14-3-3σ, γ-H2AX, a phosphorylated histone marking double strand DNA breaks, and phosphorylated ataxia telangiectasia mutated (ATM) protein were all increased. cGAS-STING-interferon signaling was impaired in AD and was accompanied by a depletion of STING protein from Golgi and a failure to elevate interferon despite the presence of DSBs. The results suggest that oxidation of p53 by ROS could inhibit the DDR and decrease its ability to orchestrate DSB repair by altering the oligomerization state of p53. The failure of immune-stimulated DNA repair may contribute to cell loss in AD and suggests new therapeutic targets for AD.

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Section: Discussionmentioning

confidence: 99%

Sting and p53 DNA repair pathways are compromised in Alzheimer’s disease

Nelson

2023

Sci Rep

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“…Moreover, A β has been found to indirectly partially unblock synaptic NMDA receptors [ 82 ], which are known to make an essential contribution to spatial working memory processing [ 83 ]. A β also activates metabotropic glutamate receptors [ 84 ], which result in increased internalization of AMPA receptors and a shift in signaling cascades toward pathways involved in the induction of LTD and synaptic loss [ 30 , 85 , 86 ]. This effect, along with the BCM theory, could partially explain why our female and male A β 1–42 treated animals displayed LTD instead of the expected LTP following the HFS protocol.…”

Section: Discussionmentioning

confidence: 99%

Systematic characterization of a non-transgenic Aβ1–42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

Jiménez-Herrera,

Contreras,

Djebari

et al. 2023

Biol Sex Differ

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Background The amyloid-β (Aβ) cascade is one of the most studied theories linked to AD. In multiple models, Aβ accumulation and dyshomeostasis have shown a key role in AD onset, leading to excitatory/inhibitory imbalance, the impairments of synaptic plasticity and oscillatory activity, and memory deficits. Despite the higher prevalence of Alzheimer’s disease (AD) in women compared to men, the possible sex difference is scarcely explored and the information from amyloidosis transgenic mice models is contradictory. Thus, given the lack of data regarding the early stages of amyloidosis in female mice, the aim of this study was to systematically characterize the effect of an intracerebroventricular (icv.) injection of Aβ1–42 on hippocampal-dependent memory, and on associated activity-dependent synaptic plasticity in the hippocampal CA1–CA3 synapse, in both male and female mice. Methods To do so, we evaluated long term potentiation (LTP) with ex vivo electrophysiological recordings as well as encoding and retrieval of spatial (working, short- and long-term) and exploratory habituation memories using Barnes maze and object location, or open field habituation tasks, respectively. Results Aβ1–42 administration impaired all forms of memory evaluated in this work, regardless of sex. This effect was displayed in a long-lasting manner (up to 17 days post-injection). LTP was inhibited at a postsynaptic level, both in males and females, and a long-term depression (LTD) was induced for the same prolonged period, which could underlie memory deficits. Conclusions In conclusion, our results provide further evidence on the shifting of LTP/LTD threshold due to a single icv. Aβ1–42 injection, which underly cognitive deficits in the early stages of AD. These long-lasting cognitive and functional alterations in males and females validate this model for the study of early amyloidosis in both sexes, thus offering a solid alternative to the inconsistence of amyloidosis transgenic mice models.

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“…1 It cannot be unequivocally stated that the role of Aβ alone in the pathogenesis of AD is the most important. At the (Wiatrak & Balon, 2021;Wiatrak et al, 2022c) Another important research direction in AD is the search for neuroprotective factors, which are sought among molecules with anti-inflammatory properties. Other substances with neuroprotective and antiinflammatory properties include two derivatives of ascorbic acid that can cross the blood-brain barrier.…”

Section: Ad Inflammatory Mechanisms and Potential Therapeutic Strategiesmentioning

confidence: 99%

Does Inflammation Play a Major Role in the Pathogenesis of Alzheimer's Disease?

et al. 2023

Self Cite

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Alzheimer's disease (AD) is a neurodegenerative disease leading to dementia for which no effective medicine exists. Currently, the goal of therapy is only to slow down the inevitable progression of the disease and reduce some symptoms. AD causes the accumulation of proteins with the pathological structure of Aβ and tau and the induction of inflammation of nerves in the brain, which lead to the death of neurons. The activated microglial cells produce pro-inflammatory cytokines that induce a chronic inflammatory response and mediate synapse damage and the neuronal death. Neuroinflammation has been an often ignored aspect of ongoing AD research. There are more and more scientific papers taking into account the aspect of neuroinflammation in the pathogenesis of AD, although there are no unambiguous results regarding the impact of comorbidities or gender differences. This publication concerns a critical look at the role of inflammation in the progression of AD, based on the results of our own in vitro studies using model cell cultures and other researchers.

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Impact of NMDA receptor activation on DNA damage in PC12 neuron-like cell cultures in the presence of β-amyloid peptides

Cited by 5 publications

References 51 publications

Sting and p53 DNA repair pathways are compromised in Alzheimer’s disease

Sting and p53 DNA repair pathways are compromised in Alzheimer’s disease

Systematic characterization of a non-transgenic Aβ1–42 amyloidosis model: synaptic plasticity and memory deficits in female and male mice

Does Inflammation Play a Major Role in the Pathogenesis of Alzheimer's Disease?

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