Identifying genes and pathways underlying Alzheimer’s regional vulnerability.

We are trying to understand the mechanisms responsible for the loss of cognitive abilities that accompany aging. In an early work we reported that brain aging is paralleled by the gradual but persistent change in the cholesterol levels in the plasma membrane of hippocampal neurons, both in vitro and in situ (Martin et al., 2008), an area of the brain with implications in learning and memory. We then demonstrated that much of this loss is due to the transcriptional up-regulation of a gene involved in cholesterol hydroxylation: 24 cholesterol hydroxylase, or Cyp46A1,  in turn the consequence of metabolic stress from excitatory neurotransmission, therefore the accumulated physiological response to normal brain activity (Sodero et al., 2011, 2012). In functional terms, the change in cholesterol/sphingomyelin content increases the clustering of receptor tyrosine kinase in the plasma membrane of the aging neurons, especially TrkB, helping the survival response of old neurons to exogenous stressors (Martin et al., 2011). On the negative side, cholesterol alterations with age results in impaired lateral mobility and internalization of glutamate receptors of the AMPA type, reducing the capacity of old neurons to efficiently support certain forms of electrical response involved in learning and memory (Martin et al., under consideration). At the molecular level, the lipid imbalance occurring with age leads to the diffusion away from synaptic sites of the cholesterol and PI(4,5)P2 binding molecule MARCKS. Such loss impacts on the amount of PI(4,5)P2 to be hydrolyzed by PLCg and therefore reduced synaptic plasticity processes (Trovo et al., 2013).

References

Martin, M., Perga, S., Trovo, L., Rasola, A., Holm, P., Rantamäki, T., Harkany, T., Castrén, E., Chiara, F. and Dotti, C.G. (2008) Cholesterol loss enhances TrkB signaling in hippocampal neurons aging in vitro. Mol. Biol. of the Cell 19(5); 2101-2112

Martin MG, Trovo' L, Perga S, Sadowska A, Rasola A, Chiara F and Dotti C.G. (2011) Cyp46-mediated cholesterol loss promotes survival in stressed hippocampal neurons. Neurobiol. Aging. 32(5):933-43.

Sodero, A.O., Weissmann, C., Ledesma, M.D. and Dotti, C.G. (2011) Metabolic stress from excitatory neurotransmission contributes to cholesterol loss in hippocampal neurons in vitro. Neurobiol. Aging 32(6):1043-53.

Sodero, A., Vriens, J., Ghosh, D., Stegner, D., Brachet, A., Pallotto, M., Sassoe-Pognetto, M., Browers, J.,F., Helms, J.B.,Nieswandt, B., Voets, T. and Dotti, C.G. (2012). Cholesterol loss during glutamate-mediated excitotoxicity. EMBO J.31, 1764-1773

Trovò, L., Ahmed, T., Callaerts-Vegh, Z., Buzzi, A., Bagni, C., Chua, M., VanDenDriesche, T., D’Hooge, R., Balschum, D., and Dotti, C.G. (2013). Low hippocampal PI(4,5)P2 contributes to reduced cognition in old mice due to loss of MARCKS. Nature Neuroscience. 16 (4): 449-55.

Carlos Dotti laboratory web: cbm.uam.es/cdottilab