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

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

doi:10.3233/JAD-201264

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

Journal

Journal of Alzheimer's Disease

ISSN

1387-2877

1875-8908

Date Issued

2021

Author(s)

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

Facultad de Medicina Clínica Alemana Universidad del Desarrollo

Carol D. SanMartín

Melissa Nassif

Type

Resource Types::text::journal::journal article

DOI

10.3233/JAD-201264

URL

https://investigadores.udd.cl/handle/123456789/7307

Abstract

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.