Epigenetic consequences of cholesterol loss in the aging brain

MAURICIO G MARTÍN

Simposio; Reunión Anual de la de la Sociedad Argentina de Fisiología; 2019

Agingis characterized by a progressive decline in cognitive capacities. Severalrecent reports indicate that epigenetic mechanisms are affected in the agedbrain and contribute to the aged brain phenotype. It is, however, unclearwhether or not and how typical features of old neurons alter the epigeneticregulation of learning and memory genes. We have analyzed the effect of changesin lipid composition in the brain, a constitutive feature of aging, on the epigeneticregulation of gene expression. We found that neuronal cholesterol loss impairsthe proper function of neuronal receptors and downstream signaling pathwaysleading to the formation of a repressive chromatin structure in old neurons. Inaddition, altered levels of sphingolipid metabolizing enzymes contribute togene repression by increasing histone deacetylase activity. Oral administrationof Voriconazole, an inhibitor of the cholesterol catabolic enzymecholesterol-24-hydroxylase in mammalian brain, rescued hippocampal age-associatedcholesterol loss and improved cognitive abilities of old mice. These results contributeto unveil some of the mechanisms involved in the cognitive decline of the old.<!-- /* Font Definitions */ @font-face{font-family:"Cambria Math";panose-1:2 4 5 3 5 4 6 3 2 4;mso-font-charset:0;mso-generic-font-family:roman;mso-font-pitch:variable;mso-font-signature:3 0 0 0 1 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal{mso-style-unhide:no;mso-style-qformat:yes;mso-style-parent:"";margin:0cm;margin-bottom:.0001pt;mso-pagination:widow-orphan;font-size:12.0pt;font-family:"Times New Roman",serif;mso-fareast-font-family:"Times New Roman";mso-ansi-language:EN-GB;}.MsoChpDefault{mso-style-type:export-only;mso-default-props:yes;font-family:"Cambria",serif;mso-ascii-font-family:Cambria;mso-ascii-theme-font:minor-latin;mso-fareast-font-family:"MS Mincho";mso-fareast-theme-font:minor-fareast;mso-hansi-font-family:Cambria;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:"Times New Roman";mso-bidi-theme-font:minor-bidi;mso-ansi-language:ES-TRAD;mso-fareast-language:ES;}size:595.0pt 842.0pt;margin:70.85pt 3.0cm 70.85pt 2.0cm;mso-header-margin:35.4pt;mso-footer-margin:35.4pt;mso-paper-source:0;}div.WordSection1{page:WordSection1;}