Synaptic dysfunctions in the aging brain: implications for AD.
Our research group is interested in the molecular and cellular mechanisms underlying synaptic plasticity, a process widely believed as the basis for learning and memory. It is also appreciated that many aging-related neurodegenerative disorders may have a synaptic dysfunction as their primary origin, which is probably responsible for the early cognitive deficits of the disease. In particular, we are investigating aging-associated alterations in synaptic plasticity mechanisms as a potential cause of sporadic Alzheimer’s disease, and possibly of other aging-related forms of cognitive decline.
This research theme is advancing on several parallel fronts. On the one hand, we are using Alzheimer’s disease mouse models and hippocampal slice cultures, to explore alterations in synaptic plasticity mechanisms triggered by neuronal exposure to beta-amyloid, one of the key pathological agents in Alzheimer’s disease. In addition, we are focusing on the PI3K-PTEN signaling pathway and its alterations in aging neurons. This pathway controls specific forms of synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD), and at the same time is a critical mediator of neuroprotective and neurodegenerative events associated to aging. Therefore, these investigations are allowing us to better understand synaptic plasticity signaling within the context of physiological aging and pathological alterations, such as Alzheimer’s disease.
Publications with acknowledgment to Consolider funding
- Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement. Knafo S, Venero C, Sánchez-Puelles C, Pereda-Peréz I, Franco A, Sandi C, Suárez LM, Solís JM, Alonso-Nanclares L, Martín ED, Merino-Serrais P, Borcel E, Li S, Chen Y, Gonzalez-Soriano J, Berezin V, Bock E, Defelipe J, Esteban JA. PLoS Biol. 10:e1001262. doi: 10.1371/journal.pbio.1001262, 2012.
- The balance between receptor recycling and trafficking toward lysosomes determines synaptic strength during long-term depression. Fernández-Monreal M, Brown TC, Royo M, Esteban JA. J Neurosci 32, 13200-13205, 2013.
- MAP1B-dependent Rac activation is required for AMPA receptor endocytosis during long-term depression. Benoist M, Palenzuela R, Rozas C, Rojas P, Tortosa E, Morales B, González-Billault C, Ávila J, Esteban JA. EMBO J 32, 2287-2299, 2013.
- Ghrelin triggers the synaptic incorporation of AMPA receptors in the hippocampus. Ribeiro LF, Catarino T, Santos SD, Benoist M, van Leeuwen JF, Esteban JA, Carvalho AL. PNAS 111, E149-E158, 2014.
Esteban laboratory web: www.cbm.uam.es/estebanlab