Cellular and Molecular Neurobiology
Author: LEANDRO GERMAN ALLENDE | email: lallende@immf.uncor.edu
LEANDRO G. ALLENDE 1°, MAURICIO G. MARTÍN 1°
1° Instituto de Investigación Médica Mercedes y Martín Ferreyra – INIMEC-CONICET-UNC
The brain is the most cholesterol-rich organ in the human body, containing about 25% of the bodys total cholesterol. In neurons, cholesterol has been shown to play a critical role in neurite growth, synaptogenesis, and the proper function of pre and post-synaptic compartments. Due to the incapacity of cholesterol to cross the blood-brain barrier, the brain cholesterol homeostasis is strictly controlled through synthesis de novo, mainly carried out by glial cells. Mature neurons depend mainly of cholesterol synthesized by astrocytes, which is imported in the form of ApoE-Cholesterol complexes. Once endocytosed, the cholesterol is released from the endolysosomal system by the cooperative action of the Niemann-Pick Type C proteins 1 and 2 (NPC1 and NPC2), which allow the incorporation of this lipid into the intracellular pool. In this work we show that aging results in increased miR33 which triggers a Niemann Pick phenotype in senescent astrocytes which accumulate cholesterol in lysosomal compartments. Furthermore using astrocyte-neuron cocultures we found that the cholesterol delivery from astrocytes to neurons is also impaired in astrocytes aged in vitro. Interestingly, cholesterol accumulation in aged astrocytes could be alleviated by endocannabinoid treatment. We believe that understanding these mechanisms will allow the identification of new targets for therapies or prevention of central nervous system pathologies associated with aging.