DNA damage and apoptosis in Alzheimer's disease: colocalization with c- Jun immunoreactivity, relationship to brain area, and effect of postmortem delay

AbstractIn 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6′-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5–1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42as anin vitromodel of memory disturbance in Alzheimer’s disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer’s disease.

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ChK1 Activation Induces Reactive Astrogliosis Through CIP2A/PP2A/STAT3 Pathway In Alzheimer's Disease

10.21203/rs.3.rs-877963/v1 ◽

2021 ◽

Author(s):

Ying Zhou ◽

Xiaoyuan Liu ◽

Shuqing Ma ◽

Dichen Yang ◽

Nan Zhang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Damage ◽

Cognitive Deficits ◽

Immunofluorescent Staining ◽

Experimental Conditions ◽

Stat3 Pathway ◽

Reactive Astrogliosis

Abstract Background: In Alzheimer’s disease (AD), activation of astrocyte participates in the development of neurodegenerative diseases through neuroinflammation and disturbs glia-neuron interaction. Cancerous Inhibitor of PP2A (CIP2A) is an endogenous PP2A inhibitor. CIP2A upregulation specifically in astrocytes causes reactive astrogliosis, synaptic degeneration and cognitive deficits. However, the underlying mechanism of CIP2A upregulation remains unclear. Methods: In 3xTg-AD mice, we determined ChK1 was activated and related to DNA damage upregulating CIP2A by WB. We transfected EGFP-ChK1 plasmid into HEK293-T cell to determine ChK1 induces CIP2A upregulation and PP2A inhibition. We incubated Aβ and infected GFAP-ChK1-LV into primary astrocytes to confirm the signaling pathway in astrocytes and astrogliosis in AD. GFAP-ChK1-AAV was injected into C57/BL6 mice to induce specific expression of target protein in astrocytes. ChK1 inhibitor (SB) was performed to reverse the ChK1 activity. Outcomes were assessed using molecular (immunofluorescent staining, Western Blot and Golgi staining) measures to estimate symptomatic pathology and behavioral (NORT, OLT, MWM and FCT) measures to assess cognitive function. For most experiments, subjects were randomly assigned to experimental groups, and data were collected under blinded experimental conditions.Results: We demonstrated that DNA damage related Checkpoint kinase 1 (ChK1) was activated in 3xTg-AD mice. ChK1-mediated CIP2A overexpression drove inhibition of PP2A and activated STAT3, then led to reactive astrogliosis and neurodegeneration in vitro. Infection of mouse brain with GFAP-ChK1-AAV induced AD-like cognitive deficits and exacerbated AD pathologies in vivo. In conclusion, we showed that ChK1 activation induced reactive astrogliosis, degeneration of neurons and deterioration of AD through CIP2A-PP2A-STAT3 pathway, and inhibiting ChK1 might be a potential therapeutic approach for AD treatment.Conclusions: These results suggest that ChK1 is upregulated in 3xTg-AD mice, ChK1-mediated CIP2A overexpression drives inhibition of PP2A and activates STAT3, then leads to reactive astrogliosis, neurodegeneration and AD-like cognitive deficits in vitro and in vivo.

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Selective impairment of p53-mediated cell death in fibroblasts from sporadic Alzheimer's disease patients

Journal of Cell Science ◽

10.1242/jcs.115.15.3131 ◽

2002 ◽

Vol 115 (15) ◽

pp. 3131-3138

Author(s):

Daniela Uberti ◽

Teresina Carsana ◽

Enza Bernardi ◽

Luigi Rodella ◽

Piergiovanni Grigolato ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Cell Cycle ◽

Alzheimer's Disease ◽

Dna Damage ◽

Target Genes ◽

Oxidative Injury ◽

Protective Mechanism ◽

Human Skin Fibroblast ◽

H2o2 Treatment ◽

Specific Alteration

In this study, we evaluated the response of different human skin fibroblast cultures obtained from eight probable Alzheimer's disease patients and eight non-Alzheimer's disease subjects to an acute oxidative injury elicited by H2O2. This treatment generates reactive oxygen species,which are responsible for DNA damage and apoptosis. To compare the sensitivity of fibroblasts from Alzheimer's disease or non-Alzheimer's disease patients to H2O2 exposure, we evaluated different parameters,including cell viability, the extension of DNA damage and the ability of the cells to arrest proliferation and to activate an apoptotic program. We found that fibroblasts from Alzheimer's disease patients were more resistant that those from control subjects to H2O2 treatment, although the extent of DNA damage induced by the oxidative injury was similar in both experimental groups. The protective mechanism of Alzheimer's disease fibroblasts was related to an impairment of H2O2-induced cell cycle arrest and characterized by an accelerated re-entry into the cell cycle and a diminished induction of apoptosis. Fibroblasts from Alzheimer's disease patients also have a profound impairment in the H2O2-activated, p53-dependent pathway, which results in a lack of activation of p53 or p53-target genes, including p21,GADD45 and bax. This study demonstrates a specific alteration of an intracellular pathway involved in sensing and repairing DNA damage in peripheral cells from Alzheimer's disease patients.

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NOVEL BIODEVICE RELEASES DRUG IN VIVO FOR 14 DAYS AND AVOIDS DNA DAMAGE IN STRESS-INDUCED NEUROBLASTOMA CELLS: A PROMISE FOR ALZHEIMER'S DISEASE TREATMENT

Alzheimer s & Dementia ◽

10.1016/j.jalz.2017.06.1273 ◽

2017 ◽

Vol 13 (7) ◽

pp. P955-P956 ◽

Cited By ~ 1

Author(s):

Geisa Nogueira Salles ◽

Cristina Pacheco-Soares ◽

Michele Longoni Calió ◽

Fernanda Roberta Marciano ◽

Christian Holscher ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dna Damage ◽

Neuroblastoma Cells ◽

Disease Treatment

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Ensembles of Deep Learning Architectures for the Early Diagnosis of the Alzheimer’s Disease

International Journal of Neural Systems ◽

10.1142/s0129065716500258 ◽

2016 ◽

Vol 26 (07) ◽

pp. 1650025 ◽

Cited By ~ 127

Author(s):

Andrés Ortiz ◽

Jorge Munilla ◽

Juan M. Górriz ◽

Javier Ramírez

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Deep Learning ◽

Early Diagnosis ◽

Brain Area ◽

Brain Regions ◽

Belief Networks ◽

Deep Belief Networks ◽

Learning Architectures ◽

Aided Diagnosis

Computer Aided Diagnosis (CAD) constitutes an important tool for the early diagnosis of Alzheimer’s Disease (AD), which, in turn, allows the application of treatments that can be simpler and more likely to be effective. This paper explores the construction of classification methods based on deep learning architectures applied on brain regions defined by the Automated Anatomical Labeling (AAL). Gray Matter (GM) images from each brain area have been split into 3D patches according to the regions defined by the AAL atlas and these patches are used to train different deep belief networks. An ensemble of deep belief networks is then composed where the final prediction is determined by a voting scheme. Two deep learning based structures and four different voting schemes are implemented and compared, giving as a result a potent classification architecture where discriminative features are computed in an unsupervised fashion. The resulting method has been evaluated using a large dataset from the Alzheimer’s disease Neuroimaging Initiative (ADNI). Classification results assessed by cross-validation prove that the proposed method is not only valid for differentiate between controls (NC) and AD images, but it also provides good performances when tested for the more challenging case of classifying Mild Cognitive Impairment (MCI) Subjects. In particular, the classification architecture provides accuracy values up to 0.90 and AUC of 0.95 for NC/AD classification, 0.84 and AUC of 0.91 for stable MCI/AD classification and 0.83 and AUC of 0.95 for NC/MCI converters classification.

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