Combating age-dependent deficits in synaptic plasticity and cognition by preventing cholesterol loss in the neuronal plasma membrane.

Learning and memory decline with age. The same can be observed if cellular models of learning and memory are used, such as long-term potentiation (LTP) and long-term depression (LTD), which represent the most established models. We have recently demonstrated that loss of MARCKS protein, which is intricately associated with neuronal membranes, is one key factor in this dysfunction in aged animals (Trovo et al., 2013). We aim to elucidate the mechanisms underlying the loss of this protein. Provisional evidence indicates that cholesterol homeostasis is a key determinant in this process: a) MARCKS requires cholesterol-rich microdomains at the plasma membrane to exert its role and b) the synthesis of the neuron-specific enzyme CYP46A1 that is responsible for the majority of cholesterol turnover, increases in the aged brain (Martin et al., 2010). Thus, we hypothesize that reduced cholesterol incorporation into neuronal plasma membranes and a disturbed lipid homeostasis might be central to MARCKS loss with aging and, by virtue of it, overt functional deficits during aging such as impaired synaptic plasticity and cognition. We will test this hypothesis by manipulating the cholesterol membrane content by various means, pharmacological and molecular and in different experimental systems, in vitro and in vivo. The detailed mechanistic knowledge at the end of the project will be used to screen for specific inhibitors of cholesterol loss as a basis for anti-cognition-loss therapeutics.