Membrane lipid changes of the aged brain: role in synaptic dysfunction and relation to AD pathology.
The aim of this workpackage is to understand how normally occurring lipid changes typical of the aged brain relate to synaptic organization and function at this stage of life and to which extent any alteration in this process could transform a “normal” dysfunctional aged brain into a “pathological” one. Our research focuses in: i) characterizing the lipidomics of the aged neuron, ii) identifying the causes and consequences of age-related lipid changes and iii) establishing strategies to revert or delay these changes and their consequences.
The results obtained so far identify alterations in the levels and/or localization of cholesterol, sphingomyelin and phosphoinositides in the aging brain and offer insight into the molecular mechanisms by which these alterations promote the appearance of aging signs (i.e. synaptic dysfunction, cognitive deficits, response to stress, protein aggregation, autophagy deficiencies and Alzheimer´s disease (AD) hallmarks). The results also validate seladin1 and acid sphingomyelinase deficient mice and organotypic rodent hippocampal slices as in vivo and ex vivo models to analyze aging. In addition, experiments carried out in vitro and in vivo set the basis for lipid modifying strategies leading to prevent or delay age/AD related brain dysfunction.
Collaborations with other groups of the Consolider consortium are instrumental to reach our goals. Current collaborations have been established with the groups of:
Jose Antonio Esteban, on the influence of age related lipid changes in Neurotransmitter receptors and on the characterization of rodent organotypic hippocampal slices as an ex vivo model to study aging
Coral SanFeliu, on the characterization of SAMP8 mice as a lipid related aging model
Patricia Boya, on the autophagy alterations promoted by lipid changes
Enrique de la Rosa, on retinal anomalies in lipid mouse models
Maria Ángeles Moro, on the vulnerability to stress/hipoxia of lipid related mouse models
Ángel Nebreda, on lipid modulation of p38/MAPK mediated signaling
Dolores Ledesma laboratory web: cbm.uam.es/Dledesmalab