Publication:
Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory-entorhinal-amygdaloid axis in Alzheimer's and Parkinson's diseases

Date

2023

Director

Publisher

BMC
Acceso abierto / Sarbide irekia
Artículo / Artikulua
Versión publicada / Argitaratu den bertsioa

Project identifier

MICINN/ Plan Nacional de I+D+i 2017-2020/ RED2018-102662-T
AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110356RB-I00/ES/recolecta
Gobierno de Navarra//0011-1411-2020-000028
Métricas Alternativas

Abstract

Background Smell impairment is one of the earliest features in Alzheimer’s (AD) and Parkinson’s diseases (PD). Due to sex diferences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated with olfactory dysfunction. Methods SWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workfows were applied in 57 post-mortem olfactory tracts (OT) derived from controls with no known neurological history (n=6F/11M), AD (n=4F/13M) and PD (n=7F/16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas. Results 327 and 151 OT diferentially expressed proteins (DEPs) were observed in AD women and AD men, respec‑ tively (35 DEPs in common). With respect to PD, 198 DEPs were identifed in PD women, whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interac‑ tion networks and widespread sex-dependent pathway perturbations in a disease-specifc manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profle across the olfactory–entorhinal–amygdaloid axis, evidencing disease-, sex- and brain structure-dependent changes in olfactory protein acetylation. Conclusions Alteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profle observed across the olfactory pathway-associated brain regions in AD and PD indicates difer‑ ential NAD (+)-dependent deacetylase mechanisms between women and men. All these data shed new light on diferential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies.

Description

Keywords

Alzheimer, Olfaction, Parkinson, Proteomics, Sexual dimorphism, Sirtuin

Department

Ciencias de la Salud / Osasun Zientziak

Faculty/School

Degree

Doctorate program

item.page.cita

Cartas-Cejudo, P., Lachén-Montes, M., Ferrer, I., Fernández-Irigoyen, J., & Santamaría, E. (2023). Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory–entorhinal–amygdaloid axis in Alzheimer’s and Parkinson’s diseases. Biology of Sex Differences, 14(1), 5. https://doi.org/10.1186/s13293-023-00487-x

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© 2023, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License.

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