miR-33 alters cholesterol transport between astrocytes and neurons in aging

LEANDRO ALLENDE; MAURICIO MARTÍN

Congreso; Reunión SAIB 2022; 2022

The brain is the most cholesterol-rich organ in the human body, containing about 25% of the body’stotal 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. Thus, the cholesterolhomeostasis has to be tightly regulated in the brain in order to avoid potential imbalances which willhave severe consequences to brain performancePrevious reports from our laboratory indicate that the decrease in neuronal cholesterol levels inaging would be related to the development of cognitive problems. Due to the incapacity ofcholesterol to cross the blood-brain barrier, the brain cholesterol homeostasis is strictly controlledthrough synthesis de novo, mainly carried out by glial cells. Mature neurons depend mainly ofcholesterol 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 cooperativeaction of the Niemann-Pick Type C proteins 1 and 2 (NPC1 and NPC2), which allow the incorporationof this lipid into the intracellular pool.In this work we show that aging results in increased miR33 which triggers a Niemann Pick phenotypein senescent astrocytes which accumulate cholesterol in lysosomal compartments. Furthermoreusing astrocyte-neuron cocultures we found that the cholesterol delivery from astrocytes to neuronsis also impaired in astrocytes aged in vitro. Interestingly, cholesterol accumulation in aged astrocytescould be alleviated by endocannabinoid treatment. We believe that understanding thesemechanisms will allow the identification of new targets for therapies or prevention of centralnervous system pathologies associated with aging.