Speaker: Carlos Dotti
VIB Department of Molecular and Developmental Genetics/ K.U.Leuven Department of Human Genetics, Leuven, Belgium

Organizer: IRB Barcelona and IBMB-CSIC
Host: Ángel Nebreda, IRB Barcelona
Date: Friday, 17 February 2012, 12:00h.
Place: Sala Fèlix Serratosa, Parc Cièntific de Barcelona, Spain

Abstract

Aging refers to the numerous changes that occur with time, most of them the consequence of accumulated damage from by-products of oxidative metabolism. Brain cells are particularly resistant to these byproducts, reflected in few dead neurons in the aged individual. Because these cells are permanently arrested in G0 and because of their high energetic demand, the strong survival capacity implies the existence of most robust survival mechanisms. We found that one such mechanism is via the regulation of the lipidic composition of the plasma membrane, more specifically a reduction in membrane cholesterol and an increase in sphingomyelin. We corroborated that these changes are the consequence of metabolic stress due to excitatory neurotransmission and involve the activation, at the promoter level, of the gene 24 hydroxy-cholesterol (Cyp46A1). Gain and loss-of-function experiments confirmed the existence of a direct cause-effect relationship between the two processe.

Moreover, we demonstrated that one consequences of the cholesterol/sphingomyelin changes is at the level of lateral diffusion of membrane receptors, which we studied by single particle tracking. In short, glutamate receptors of the AMPA type become less mobile in the synapses of old animals, in a cholesterol loss-dependent manner. This reduced mobility impacts on the capacity of neurons to “learn” (in electrical terms). Thus, electrophysiological experiments reveled that the old hippocampus is resistant to long term depression but this can be improved by restoring cholesterol levels. In addition to reduced lateral diffusion of neurotransmitter receptors, another consequence is the diffusion away from synaptic sites of the PI(4,5)P2 binding molecule MARCKS. We observed that this impacts on the amount of PLCg activated upon neurotrophin stimulation and therefore less PI(4,5)P2 hydrolysis and consequently less PKC-mediated activation of CREBS and synthesis of genes involved in learning and memory. Naturally, the loss of MARCKS form the synaptic membrane of old neurons was due to the changes in lipid that occur very early in the post-differentiation stage.

All in all, we have accumulated an important amount of information that indicates that as the brain ages it occurs a great deal of activity towards survival which, while improving survival, leads to reduced plasticity. My laboratory has two major goals for the next years: i) to identify genes and mechanisms that could improve plasticity without interfering with survival strength and ii) to determine to which extent a change in the survival and plasticity balance is at the base of sporadic Alzheimer's disease.