TY - JOUR
T1 - DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer's Disease Patients, and a Transgenic Model of the Disease
AU - Leyton, Esteban
AU - Matus, Diego
AU - Espinoza, Sandra
AU - Benitez, José Matías
AU - Cortés, Bastián I.
AU - Gomez, Wileidy
AU - Arévalo, Nohela B.
AU - Murgas, Paola
AU - Manque, Patricio
AU - Woehlbier, Ute
AU - Duran-Aniotz, Claudia
AU - Hetz, Claudio
AU - Behrens, María Isabel
AU - Sanmartín, Carol D.
AU - Nassif, Melissa
N1 - Funding Information:
We would like to acknowledge all the patients and their families for their participation in this research. The grants supporting this work were, Fondo Nacional de Desarrollo Científico y Tec-nológico, Fondecyt, from the Chilean Government, grants numbers 11160288 (MN), 11171061 (CSM), and 11190258 (PM), 1190958 (MB), 1150743 and
Publisher Copyright:
© 2021 - IOS Press. All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - DEF8
KW - Rubicon
KW - autophagy
KW - lymphocytes
KW - lysosome
KW - mild cognitive impairment
UR - http://www.scopus.com/inward/record.url?scp=85111157229&partnerID=8YFLogxK
U2 - 10.3233/JAD-201264
DO - 10.3233/JAD-201264
M3 - Article
C2 - 33612542
AN - SCOPUS:85111157229
VL - 82
SP - S163-S178
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
SN - 1387-2877
IS - s1
ER -