BEHRENS PELLEGRINO, MARIA ISABEL
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BEHRENS PELLEGRINO, MARIA ISABEL
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BEHRENS PELLEGRINO, MARIA ISABEL
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mbehrens@udd.cl
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7007110355

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Senescence Markers in Peripheral Blood Mononuclear Cells in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease

2022 , Felipe Salech , Carol D. SanMartín , Jorge Concha-Cerda , Esteban Romero-Hernández , Daniela P. Ponce , Gianella Liabeuf , Nicole K. Rogers , Paola Murgas , Bárbara Bruna , Jamileth More , BEHRENS PELLEGRINO, MARIA ISABEL

Recent studies suggest that cellular senescence plays a role in Alzheimer’s Disease (AD) pathogenesis. We hypothesize that cellular senescence markers might be tracked in the peripheral tissues of AD patients. Senescence hallmarks, including altered metabolism, cell-cycle arrest, DNA damage response (DDR) and senescence secretory associated phenotype (SASP), were measured in peripheral blood mononuclear cells (PBMCs) of healthy controls (HC), amnestic mild cognitive impairment (aMCI) and AD patients. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry, while IL-6 and IL-8 mRNA were analyzed by qPCR, and phosphorylated H2A histone family member X (γH2AX) was analyzed by immunofluorescence. Senescent cells in the brain tissue were determined with lipofuscin staining. An increase in the number of senescent cells was observed in the frontal cortex and hippocampus of advanced AD patients. PBMCs of aMCI patients, but not in AD, showed increased SA-β-Gal compared with HCs. aMCI PBMCs also had increased IL-6 and IL8 mRNA expression and number of cells arrested at G0-G1, which were absent in AD. Instead, AD PBMCs had significantly increased p16 and p53 expression and decreased γH2Ax activity compared with HC. This study reports that several markers of cellular senescence can be measured in PBMCs of aMCI and AD patients.

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Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort

2021 , Nohela B. Arévalo , Daniela P. Castillo-Godoy , Italo Espinoza-Fuenzalida , Nicole K. Rogers , Gonzalo Farias , Carolina Delgado , Mauricio Henriquez , Luisa Herrera , BEHRENS PELLEGRINO, MARIA ISABEL , Carol D. SanMartín , K.S. Jagannatha Rao , Gabrielle B. Britton , Luisa Lilia Rocha Arrieta , Norberto Garcia-Cairasco , Alberto Lazarowski , Adrián Palacios , Antoni Camins Espuny , Ricardo B. Maccioni

Background: Amyloid-β peptide (Aβ) deposition in Alzheimer’s disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. Objective: To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aβ-transporters in peripheral blood mononuclear cells (PBMCs). Methods: VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aβ-transporters were evaluated in subgroups by qPCR. Results: Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1, while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aβ-transporters in both groups. Conclusion: We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism.

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DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer’s Disease Patients, and a Transgenic Model of the Disease

2021 , Esteban Leyton , Diego Matus , Sandra Espinoza , José Matías Benitez , Bastián I. Cortés , Wileidy Gomez , Nohela B. Arévalo , Paola Murgas , Patricio Manque , Ute Woehlbier , Claudia Duran-Aniotz , Claudio Hetz , BEHRENS PELLEGRINO, MARIA ISABEL , Carol D. SanMartín , Melissa Nassif , K.S. Jagannatha Rao , Gabrielle B. Britton , Luisa Lilia Rocha Arrieta , Norberto Garcia-Cairasco , Alberto Lazarowski , Adrián Palacios , Antoni Camins Espuny , Ricardo B. Maccioni

Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer’s disease (AD). However, few studies are available concerning autophagy gene expression in AD patients. Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheral blood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. Method: By real-time PCR and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence. Results: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization. Conclusion: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD.

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Vitamin D Increases Aβ140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients

2018 , Carol D. SanMartín , Mauricio Henriquez , Carlos Chacon , Daniela P. Ponce , Felipe Salech , Nicole K. Rogers , BEHRENS PELLEGRINO, MARIA ISABEL

Background: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain. We have reported that lymphocytes from Alzheimer's disease (AD) patients have an increased susceptibility to oxidative death by H2O2 exposure, but currently it is unknown if this characteristic is modifiable in vivo. Objective: To determine if correction of low vitamin D levels protects lymphocytes from oxidative death and increases Aβ1-40 plasma levels in MCI and very early AD (VEAD) patients. Method: Sixteen MCI, 11 VEAD and 25 healthy control (HC) voluntaries were evaluated with the Clinical Dementia Rating (CDR), Montreal Cognitive assessment (MoCA), and Memory Index score (MIS). Lymphocyte death was measured by flow cytometry after 20h exposure to H2O2. In patients with low levels of vitamin D -11 MCI, 9 VEAD and 20 HC- lymphocyte H2O2-death, plasma Aβ1-40 levels and cognitive status were evaluated pre- and post-vitamin D supplementation for 6 months. Results: Lymphocytes from MCI and VEAD patients showed increased susceptibility to oxidative death at study entry. In MCI, but not VEAD patients, lymphocyte susceptibility to death and Aβ1-40 levels plasma levels improved after 6 months of vitamin D supplementation. In addition, cognitive status on follow-up (18 months) improved in MCI patients after vitamin D supplementation. Conclusion: Vitamin D supplementation may be beneficial in MCI. The lack of effect in VEAD may be due to a more advanced stage or different characteristics of the neurodegenerative process.

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Cancer Imprints an Increased PARP-1 and p53-Dependent Resistance to Oxidative Stress on Lymphocytes of Patients That Later Develop Alzheimer's Disease

2018 , Salech, Felipe , Ponce, Daniela , Carol D. SanMartín , Nicole K. Rogers , Mauricio Henríquez , BEHRENS PELLEGRINO, MARIA ISABEL

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Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease

2022 , Sandra Espinoza , Felipe Grunenwald , Wileidy Gomez , Felipe García , Lorena Abarzúa-Catalan , Sebastián Oyarce-Pezoa , Maria Fernanda Hernandez , Bastián I. Cortés , Markus Uhrig , Daniela P. Ponce , Claudia Durán-Aniotz , Claudio Hetz , Carol D. SanMartín , Victor H. Cornejo , EZQUER, EDUARDO FERNANDO , Valentina Parra , BEHRENS PELLEGRINO, MARIA ISABEL , Patricio A. Manque , Diego Rojas-Rivera , René L. Vidal , Ute Woehlbier , Melissa Nassif

Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.

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Cancer History Avoids the Increase of Senescence Markers in Peripheral Cells of Amnestic Mild Cognitive Impaired Patients

2023 , Carol D. SanMartín , Felipe Salech , Daniela Paz Ponce , Jorge Concha-Cerda , Esteban Romero-Hernández , Gianella Liabeuf , Nicole K. Rogers , Paola Murgas , Bárbara Bruna , Jamileth More , BEHRENS PELLEGRINO, MARIA ISABEL

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer’s Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer’s Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI). Cellular senescence is a regulator of susceptibility to cell death and has been related to the pathophysiology of AD and cancer. Recently, we showed that cellular senescence markers can be tracked in PBMCs of aMCI patients, so we here investigated whether these senescence markers are dependent on having a history of cancer. Senescence-associated βeta-galactosidase (SA-β-Gal) activity, G0-G1 phase cell-cycle arrest, p16 and p53 were analyzed by flow cytometry; phosphorylated H2A histone family member X (γH2AX) by immunofluorescence; IL-6 and IL-8 mRNA by qPCR; and plasmatic levels by ELISA. Senescence markers that were elevated in PBMCs of aMCI patients, such as SA-β-Gal, Go-G1 arrested cells, IL-6 and IL-8 mRNA expression, and IL-8 plasmatic levels, were decreased in PBMCs of Ca + aMCI patients to levels similar to those of controls or of cancer survivors without cognitive impairment, suggesting that cancer in the past leaves a fingerprint that can be peripherally traceable in PBMC samples. These results support the hypothesis that the senescence process might be involved in the inverse association between cancer and AD.

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