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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2021 2021 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0 1.2 1.2 1.4 1.4 1.6 1.6 1.8 1.8 2.0 2.0

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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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