LIPID AND EPIGENETIC ALTERATIONS ASSOCIATED WITH BRAIN AGING
Disruption in cholesterol homeostasis in the brain has been associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease or Amyotrophic Lateral Sclerosis and with cognitive alterations in aging. Our laboratory studies alterations in cholesterol homeostasis and their consequences on the correct function of neuronal and glial cells. One of our lines of work studies the relationship between cholesterol changes in aged neuronal membranes as a cause of epigenetic alterations in old neurons. In particular, we analyze the loss of cholesterol in old neurons as a determinant of a reduced function of neuronal receptors, which gives rise to epigenetic alterations in old neurons generating memory loss. We evaluated the use of plant sterols (phytosterols) as a dietary supplement capable of reversing these deficiencies.
Given that neuronal cells depend mainly on cholesterol synthesized in astrocytes, we analyzed cholesterol trafficking between aged astrocytes and neurons and evaluated the role of endocannabinoids as a rescue strategy that allows neurons to receive adequate amounts of cholesterol in a context of aging. In a third line of work, our laboratory studies how a pro-inflammatory environment, such as brain infections, can lead to an alteration of cholesterol homeostasis by generating oxysterols. We evaluate oxysterols as epigenetic mediators that trigger histone modification, generating a context that predisposes to the development of neurodegenerative diseases such as Alzheimer’s disease.
COMPETITIVE RESEARCH FUNDS
- Foncyt, PIP-Conicet, Secyt-UNC
PUBLICATIONS (LATEST FIVE YEARS)
- Allende L.G., Natalí L., Cragnolini A.B., Musri M.M., de Mendoza D and Martín M.G.* Impaired cholesterol transport from aged astrocytes to neurons can be rescued by cannabinoids. 2023, Biorxiv doi: https://doi.org/10.1101/2023.07.24.550299.
- Sodero, A.O., Castagna, V.C., Elorza, S.D., Gonzalez-Rodulfo S.M., Paulazo M.A., Ballestero J., Martin, M.G.*, Gomez-Casati, M.E.* Phytosterols reverse antiretroviral-induced hearing loss, with potential implications for cochlear aging. PLoS Biology, 2023, 21(8), e3002257.
- Martín, M.G.*, Dotti, C.G.* Game-changer in the fight against Huntington’s disease: Cholesterol nanoparticles restore brain function in mice. Pharmacological Research, 2023, 194, 106879
- Zlocowski N, Sosa LDV, De la Cruz-Thea B, Guido CB, Martin MG, Mukdsi JH, Torres AI, Petiti JP. 2023.The epigenetic EZH2/H3K27me3 axis modulates lactotroph tumor cell proliferation. J Endocrinol. 2023 Feb 1: JOE-22-0195. doi: 10.1530/JOE-22-0195.
- Cataldi, G, Elorza, S, Toledano-Zaragoza, A, Cragnolini, A. and Martín, MG*. 2023. Cholesterol-24-hydroxylase (CYP46) in the old brain: Analysis of positive populations and factors triggering its expression in astrocytes. Journal of Comparative Neurology 531:486–499.
- Martin MG* and Dotti CG*. Plasma membrane and brain dysfunction of the old: Do we age from our membranes? Frontiers in Cell and Developmental Biology. 2022. DOI 10.3389/fcell.2022.1031007.
- Guix FX, Marrero Capitán A, Casadomé-Perales A, Palomares-Pérez I, López del Castillo I, Miguel V, Goedeke L, Martín MG, Lamas S, Peinado H, Fernández- Hernando C and Dotti CG. 2021. Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup. Life Science Alliance, 2021, 4(8), e202101055.
- Perea Vega ML, Sanchez MS, Fernández G, Paglini MG, Martín MG and Barioglio SR. 2021. Ghrelin treatment leads to dendritic spine remodeling in hippocampal neurons and increases the expression of specific BDNF-mRNA species. Neurobiology of Learning and Memory. 107409.
- Complete and updated list available here.
