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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2022 2022 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

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Publication

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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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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