Oxidative DNA Damage Signalling in Neural Stem Cells in Alzheimer’s Disease

Kieroń, Marcelina; Żekanowski, Cezary; Falk, Anna; Wężyk, Michalina

doi:10.1155/2019/2149812

Cited by 15 publications

(11 citation statements)

References 48 publications

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“…Here, we show that Aβ toxicity induces NPCs to enter irreversible proliferative arrest with features of cellular senescence. APP/PS1 mice, which generate large amounts of brain Aβ peptide, have increased activation of ATM, an apical PI3K-like serine/threonine kinase that marks DNA lesions through phosphorylation of the histone H2A variant H2AX (γH2AX) [31][32][33][34]. DNA damage could be probably caused by the broadly demonstrated capacity of Aβ of increasing ROS production [35].…”

Section: Discussionmentioning

confidence: 99%

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer’s Disease

et al. 2021

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Neurogenesis in the adult brain takes place in two neurogenic niches: the ventricular-subventricular zone (V-SVZ) and the subgranular zone. After differentiation, neural precursor cells (neuroblasts) have to move to an adequate position, a process known as neuronal migration. Some studies show that in Alzheimer’s disease, the adult neurogenesis is impaired. Our main aim was to investigate some proteins involved both in the physiopathology of Alzheimer’s disease and in the neuronal migration process using the APP/PS1 Alzheimer’s mouse model. Progenitor migrating cells are accumulated in the V-SVZ of the APP/PS1 mice. Furthermore, we find an increase of Cdh1 levels and a decrease of Cdk5/p35 and cyclin B1, indicating that these cells have an alteration of the cell cycle, which triggers a senescence state. We find less cells in the rostral migratory stream and less mature neurons in the olfactory bulbs from APP/PS1 mice, leading to an impaired odour discriminatory ability compared with WT mice. Alzheimer’s disease mice present a deficit in cell migration from V-SVZ due to a senescent phenotype. Therefore, these results can contribute to a new approach of Alzheimer’s based on senolytic compounds or pro-neurogenic factors.

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Section: Discussionmentioning

confidence: 99%

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer’s Disease

et al. 2021

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“…However, impaired neurogenesis has been linked to neuronal death in neurodegenerative disorders, including AD [ 185 ]. Both NSC proliferation and differentiation can be inhibited by oxidative DNA damage and associated BER DNA repair mechanisms [ 186 ]. Furthermore, BER and DSB repair by SIRT6 is protective in AD due to accelerating neurogenesis of hippocampal neurons [ 187 ].…”

Section: Mechanisms Of Cell Death Induced By Dna Damage In Neurodegen...mentioning

confidence: 99%

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Shadfar

Brocardo

Atkin

2022

IJMS

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Human cells are exposed to numerous exogenous and endogenous insults every day. Unlike other molecules, DNA cannot be replaced by resynthesis, hence damage to DNA can have major consequences for the cell. The DNA damage response contains overlapping signalling networks that repair DNA and hence maintain genomic integrity, and aberrant DNA damage responses are increasingly described in neurodegenerative diseases. Furthermore, DNA repair declines during aging, which is the biggest risk factor for these conditions. If unrepaired, the accumulation of DNA damage results in death to eliminate cells with defective genomes. This is particularly important for postmitotic neurons because they have a limited capacity to proliferate, thus they must be maintained for life. Neuronal death is thus an important process in neurodegenerative disorders. In addition, the inability of neurons to divide renders them susceptible to senescence or re-entry to the cell cycle. The field of cell death has expanded significantly in recent years, and many new mechanisms have been described in various cell types, including neurons. Several of these mechanisms are linked to DNA damage. In this review, we provide an overview of the cell death pathways induced by DNA damage that are relevant to neurons and discuss the possible involvement of these mechanisms in neurodegenerative conditions.

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“…Neurons of CNS are regenerated in the adult brain via a process that is mediated by neural stem cells (NSCs); compromising neurogenesis is a cause of neurodegeneration diseases, including AD [183,184]. Oxidative DNA damage and its repairing process affect NSC proliferation and differentiation [184]. For instance, SIRT6 exerts anti-AD function in part via facilitating neurogenesis of hippocampal neurons via enhancing BER and DSB repair [182].…”

Section: A Role Of Dna Damage In Ad Via Affecting Neurogenesismentioning

confidence: 99%

Contributions of DNA Damage to Alzheimer’s Disease

Lin

Kapoor

et al. 2020

IJMS

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Alzheimer's disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.Int. J. Mol. Sci. 2020, 21, 1666 2 of 26 amyloid (senile) plaques in AD brain [9][10][11]. Furthermore, CDK5 activities affect DNA damage response [12], supporting a linkage of DNA damage with AD [13,14].Aβ peptides are directly produced by sequential cleavages of APP by βand γ-secretase; the proteolytic c-terminal fragment of APP (CTFβ) of β-secretase is cleaved within the cell membrane by γ-secretase to generate neurotoxic Aβ peptides with length ranging from 38-43 residues [15][16][17][18][19]. The 40 residue Aβ peptide (Aβ 1-40 ) is the major product, accounting for more than 50% of Aβ peptides [9,17]. Although the Aβ 1-42 peptide consists of less than 10% of Aβ peptides [16,17], it is more neurotoxic and associates with a higher risk of AD because of its propensity of aggregation [9]. The importance of Aβ in AD pathogenesis is illustrated by mutations of APP, PSEN1, and PREN2 genes in familial AD with the latter two encoding the presenilin 1 and presenilin 2 subunit of γ-secretase. Individuals with these mutations develop early onset dementia in an autosomal-dominant manner [20]; the typical onset starts between 30 and 50 years of age in PSEN1 mutant carriers with some being affected at in their 20s [20,21]. γ-secretase with mutant presenilin 1 or presenilin 2 subunit favors Aβ 1-42 production [16,17]. These genetic observations led to formation of the amyloid cascade hypothesis, in which abnormal Aβ drives AD pathogenesis via regulating other pathological events including tau pathology [22][23][24][25][26][27]. This hypothesis is supported by the similar pathological features between familial AD and sporadic late onset AD (LOAD) [20]. Although familial AD constitutes less than 1% of AD cases [28,29], the hypothesis has been widely accepted to guide research in advancing the understanding of both familial AD and LOAD in the past two decades [30,31].Nonetheless, it is becoming in...

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Oxidative DNA Damage Signalling in Neural Stem Cells in Alzheimer’s Disease

Cited by 15 publications

References 48 publications

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer’s Disease

Adult Neural Stem Cell Migration Is Impaired in a Mouse Model of Alzheimer’s Disease

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

Contributions of DNA Damage to Alzheimer’s Disease

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