BMI Seminar // Survival and plasticity in the aging brain

Learning and memory decline with age. The same can be said about long-term potentiation (LTP) and long-term depression (LTD), which are two cellular models of learning and memory. On the other hand, aging is not paralleled by neuronal loss, implying the existence of most strong survival mechanisms at the same time when synaptic function decays. It is unclear whether (and how) these two characteristic events of the old brain are molecularly linked.  We have recently demonstrated that during aging hippocampal neurons gradually lose cholesterol from the plasma membrane, being this most evident in synaptic fractions.  The cholesterol loss is compensated by the increase in other lipids (i.e. sphingomyelin) resulting in a significant change in membrane fluidity with age, naturally affecting the clustering, lateral diffusion and exo-endocytosis rates of a number of membrane receptors all in all affecting cell function.  One of the most striking functional consequences of the membrane fluidity change with age is a strong ligand-independent activation of some of the  receptor tyrosine kinase family members due to changes in receptor conformation, resulting in tonic auto-phosphorylation and the robust downstream activation of the PI3K/Akt hub. While on the one hand the activation of PI3K/Akt contributes to survival by inhibiting apoptotic pathways it produces on the other hand a reduction in the efficacy of cellular components of the cognitive process by inhibiting glutamate receptor endocytosis and thus LTD. These results indicate that cognitive loss with age is the price we pay for our neurons to stay alive.