Carlos Dotti

Effect of age on the lipid composition of the neuronal membrane: consequences for survival and plasticity

Carlos G. Dotti
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Madrid, Spain
Early work in obese and non-obese individuals demonstrated that peripheral insulin resistance develops as part of the normal aging process. Later work confirmed this observation and established that insulin resistance with age is also present in the brain. In turn, a number of studies demonstrated that brain insulin resistance plays a role in some of the cognitive deficits typical of this stage of life and in neurodegenerative diseases like Alzheimer’s disease. Mechanistically, peripheral and brain insulin resistance are linked to post-receptor desensitization. It is not known, however, how age produces this type of defect. We show that age impairs insulin-mediated synaptic plasticity (hippocampal insulin-mediated long term depression (LTD)). Mechanistically, this is due to a basal state of receptor chronic activation leading to the over activation of the PI3K/Akt/mTorC1 pathway, which leads to pathway silencing by desensitization. In turn, the small and gradual loss of plasma membrane cholesterol of hippocampal neurons that occurs during normal aging plays a role in these alterations: by Fluorescence Resonance Energy Transfer (FRET) we show that membrane fluidity perturbation due to s mild loss of cholesterol produces a change in the insulin receptor conformation state, favouring trans-membrane and cytoplasmic tail physical approximation and –ligand independent- phosphorylation. These results put the physiological process of membrane lipid remodelling at the centre of brain insulin resistance with age, resulting in a chronic activity-prone state with the consequent desensitization and loss of synaptic activation. On the other hand, the same mechanism that participates in the loss of insulin-mediated synaptic plasticity is involved in key for neuronal survival, which would imply that perhaps the loss of synaptic plasticity of the old is a necessary process to favour the survival of the individual (survival at the expense of function).