Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes

Background Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer’s disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration o...

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Autores principales: Zubillaga, Marlene, Tau, Julia, Rosa, Diana Esther, Bellini, María José, Arnal, Nathalie
Formato: Articulo
Lenguaje:Inglés
Publicado: 2024
Materias:
Biología
Cholesterol
Copper
Sexual differences
Astrocytes
Neurons
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/167623
Aporte de:
SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-167623
record_format dspace
spelling I19-R120-10915-1676232024-07-01T20:10:22Z http://sedici.unlp.edu.ar/handle/10915/167623 Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes Zubillaga, Marlene Tau, Julia Rosa, Diana Esther Bellini, María José Arnal, Nathalie 2024 2024-07-01T13:30:52Z en Biología Cholesterol Copper Sexual differences Astrocytes Neurons Background Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer’s disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis. Methods We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts. Results Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males. Conclusions Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR. Instituto de Investigaciones Bioquímicas de La Plata Facultad de Ciencias Veterinarias Articulo Articulo http://creativecommons.org/licenses/by/4.0/ Creative Commons Attribution 4.0 International (CC BY 4.0) application/pdf
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Biología
Cholesterol
Copper
Sexual differences
Astrocytes
Neurons
spellingShingle Biología
Cholesterol
Copper
Sexual differences
Astrocytes
Neurons
Zubillaga, Marlene
Tau, Julia
Rosa, Diana Esther
Bellini, María José
Arnal, Nathalie
Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
topic_facet Biología
Cholesterol
Copper
Sexual differences
Astrocytes
Neurons
description Background Cholesterol (Cho) is an essential lipophilic molecule in cells; however, both its decrease and its increase may favor the development of neurological diseases such as Alzheimer’s disease (AD). Although copper (Cu) is an essential trace metal for cells, the increased plasma concentration of its free form has been linked with AD development and severity. AD affects aged people, but its prevalence and severity are higher in women than in men. We have previously shown that Cu promotes Cho de novo synthesis in immature neurons as well as increased Cho in membrane rafts and Aβ levels in culture medium, but there are no results yet regarding sex differences in the effects of sublethal Cu exposure on Cho de novo synthesis. Methods We examined the potential sex-specific impact of sublethal Cu concentrations on de novo Cho synthesis in primary cultures of male and female astrocytes. We also explored whether this had any correlation with variations in Cho and APP levels within neuronal membrane rafts. Results Flow cytometry analysis demonstrated that Cu treatment leads to a greater increase in ROS levels in female astrocytes than in males. Furthermore, through RT-PCR analysis, we observed an upregulation of SREBP-2 and HMGCR. Consistently, we observed an increase in de novo Cho synthesis. Finally, western blot analysis indicated that the levels of ABCA1 increase after Cu treatment, accompanied by a higher release of radiolabeled Cho and an elevation in Cho and APP levels in neuronal membrane rafts. Importantly, all these results were significantly more pronounced in female astrocytes than in males. Conclusions Our findings confirm that Cu stimulates Cho synthesis in astrocytes, both in a ROS-dependent and -independent manner. Moreover, female astrocytes displayed elevated levels of HMGCR, and de novo Cho synthesis compared to males following TBH and Cu treatments. This corresponds with higher levels of Cho released into the culture medium and a more significant Cho and APP rise within neuronal rafts. We consider that the increased risk of AD in females partly arises from sex-specific responses to metals and/or exogenous substances, impacting key enzyme regulation in various biochemical pathways, including HMGCR.
format Articulo
Articulo
author Zubillaga, Marlene
Tau, Julia
Rosa, Diana Esther
Bellini, María José
Arnal, Nathalie
author_facet Zubillaga, Marlene
Tau, Julia
Rosa, Diana Esther
Bellini, María José
Arnal, Nathalie
author_sort Zubillaga, Marlene
title Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
title_short Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
title_full Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
title_fullStr Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
title_full_unstemmed Sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
title_sort sex‑dependent effect of sublethal copper concentrations on de novo cholesterol synthesis in astrocytes and their possible links to variations in cholesterol and amyloid precursor protein levels in neuronal membranes
publishDate 2024
url http://sedici.unlp.edu.ar/handle/10915/167623
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