Cholesterol loss during aging in hippocampal neurons. Causes and consequences

MAURICIO GERARDO MARTÍN

Seminario; Ciclo de Seminarios del Centro de Biología Molecular Severo Ochoa; 2011

The expression of cholesterol 24-hydroxylase (CYP46) increases by stress and during aging, in humans and rodents, resulting in reduced cholesterol levels in brain structures such as the hippocampus. This finding led us to hypothesize that decreased cholesterol in neuronal membranes may be responsible for some of the functional deficits typical of aging, such as synaptic plasticity. We here show that the reduced capacity of hippocampal neurons from old mice to express long term depression (LTD) can be recovered by perfusion in the hippocampus of cholesterol. Accordingly, ventricular perfusion of cholesterol improves learning and memory in old rats. Mechanistically, the old neurons? impaired LTD is accompanied by reduced glutamate-triggered AMPA receptor lateral diffusion: this process is reversed by cholesterol replenishment or by Cyp46 knock-down. These results unveil one of the mechanisms behind synaptic dysfunction during aging and suggest that brain cholesterol replenishment may be a valuable strategy to prevent cognition impairment.