Epigenetic consequences of cholesterol loss in the aging brain

MAURICIO G MARTÍN

Carlos Paz

Simposio; Reunión Anual de la Sociedad Argentina de Neurociencias; 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 brain neurons, i.e. reducedproteasomal activity, impaired mitochondrial function, altered lipidcomposition, participate in the epigenetic regulation of learning-memory genes.We have analyzed the effect of hippocampal membrane cholesterol loss, aconstitutive feature in aging, on the epigenetic regulation of the Bdnfgene.  We found that hippocampal membranecholesterol loss induces a repressive chromatin structure in old neurons and diminishesBdnf transcription. Oral administration of Voriconazole, an inhibitor of thecholesterol catabolic enzyme cholesterol-24-hydroxylase in mammalian brain,rescued hippocampal age-associated cholesterol loss, Bdnf expression andimproved cognitive abilities of old mice. These results unveil one of themechanisms involved in the cognitive decline of the old and propose Cyp46A1inhibition as valuable therapeutic possibility.<!-- /* 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;}