Brain dysfunction during ageing: Effects of membrane cholesterol loss in synaptic plasticity

ISABEL SALAS; MAURICIO GERARDO MARTÍN; CARLOS G DOTTI

Workshop; MEMBRAE TRAFFIC AT THE SYAPSE. THE CELL BIOLOGY OF SYAPTIC PLASTICITY; 2013

Brain ageing is accompanied by a loss in membrane cholesterol in the neurons of the hippocampus, a brain area important for learning and memory. Recent data suggest that ageassociated membrane cholesterol loss may be responsible for the impaired long-term depression (LTD), an electrical feature of the learning and memory process, observed at this stage of life. Postsynaptic density 95 (PSD95) protein and A-kinase anchor protein (AKAP150) are scaffolding proteins found in the postsynaptic membrane involved in AMPA receptor (AMPAR) clustering, a process highly dependent on intact cholesterol-rich membrane micro-domains. Upon LTD induction, PSD95 is degraded, AKAP150 translocates from spines and AMPARs are removed from synapses. In this study, we report cholesterol- dependent alterations in these processes. Specifically, cultured hippocampal neurons with a reduced cholesterol content to mimic the situation in the old brain, present impaired PSD95 and AKAP150 translocation from the spines after the induction of LTD with NMDA. Ageing is also associated with a reduction of PI (4,5) P2 (PIP2) in the hippocampal membrane due to a loss of its clustering molecule myristoylated alanine-rich C kinase substrate (MARCKS), resulting in the impaired long-term potentiation (LTP) of old animals. We also report that reduced hippocampal cholesterol is a sufficient sign to determine membrane MARCKS detachment.