Research

Mechanisms of synaptic dysfunction
and neurodegeneration in Alzheimer’s disease

Our research efforts focus on understanding how neurons and neuronal circuits function during memory processing and storage in order to understand the cellular and molecular mechanisms involved in brain dysfunction, memory loss and neurodegeneration in age-related cognitive disorders.

Our recent transcriptomic and molecular studies suggest that specific neuronal gene expression programs are essential for neuronal survival and memory processing, whereas deregulation of these programs causes memory impairment at early Alzheimer’s disease pathological stages. We specifically investigate the role of the transcription factor cAMP-response element binding protein (CREB) and its coactivators (CBP, CRTC) on regulating gene expression programs essential for neuronal function and survival.

Franco R., Aguinaga D., Reyes I., Canela EI., Lillo J., Tarutani A., Hasegawa M., Del Ser-Badia A., del Rio J.A, Kreutz M.R., Saura C.A., Navarro G. N-methyl-D-aspartate receptor link to the MAP kinase pathway in cortical and hippocampal neurons and microglia is dependent on calcium sensors and is blocked by α-synuclein, Tau and phospho-Tau in non-transgenic and transgenic APPSw,Ind mice.
Front Mol Neurosci. 2018, 11:273. doi: 10.3389/fnmol.2018.00273.

Van der Jeugd A., Parra-Damas A., Baeta-Corral R., Soto-Faguás CM., Ahmed T., LaFerla FM., Giménez Llort L., D’Hooge R., Saura C.A Reversal of memory and neuropsychiatric-like symptoms and reduced tau pathology by selenium treatment in 3xTg-AD mice.  
Sci Reports. 2018, 8:6431.doi: 10.1038/s41598-018-24741-0

Servián-Morilla E., Robles-Lanuza E., Sanchez-Hidalgo AC., Camacho-García RJ., Paez-Gómez JA., Mavillard F., Saura C.A, Martinez-Mir A. and Scholl FG. Proteolytic processing of neurexins by presenilins sustains synaptic vesicle release.  
J. Neurosci. 2018, 38(4):901-17.doi: 10.1523/JNEUROSCI.1357-17.2017

Parra-Damas A, Rubió-Ferrarons L, Shen J, Saura CA CRTC1 mediates preferential transcription at neuronal activity-regulated CRE/TATA promoters.  
Sci Rep. 2017 Dec 21;7(1):18004. doi: 10.1038/s41598-017-18215-y

Parra-Damas A., Chen M., Enríquez-Barreto L., Ortega L., Acosta S., Camats Perna J., Fullana N, Aguilera J., Rodríguez-Alvarez J, and Saura C.A. CRTC1 function during memory encoding is disrupted in neurodegeneration.  
Biological Psychiatry 2017, 81(2):111-123.doi: 10.1016/j.biopsych.2016.06.025

Sarroca S., Molina-Martínez P., Aresté C., Etzrodt M., García de Frutos P., Gasa R., Antonell A., Molinuevo JL, Sánchez-Valle R., Saura C.A., Lladó A., Sanfeliu C. Preservation of cell survival mechanisms by the presenilin-1 K239N mutation may cause its milder clinical phenotype.  
Neurobiology of Aging 2016, 46: 169-179.doi:10.1016/j.neurobiolaging.2016.07.002

Parra-Damas A., Valero J., Chen M., España J., Martin E., Ferrer I., Rodríguez-Alvarez J. and Saura C.A.  Crtc1 activates a transcriptional program deregulated at early Alzheimer’s disease-related stages  
J Neurosci
. 2014, 34(17):5776-87. Featured cover.  doi: 10.1523/JNEUROSCI.5288-13.2014

Xifró X., Miñano-Molina A.J., Saura C.A., Rodríguez-Álvarez J. Ras protein activation is a key event in activity-dependent survival of cerebellar granule neurons. 
J Biol Chem
. 2014, 289(12):8462-72 doi: 10.1074/jbc.M113.536375

Fadó R., Moubarak R.S., Miñano-Molina, A. J., Barneda-Zahonero B., Valero J., Saura C.A., Moran J., Comella J.C. and Rodríguez-Álvarez J. X-linked Inhibitor of Apoptosis Protein negatively regulates neuronal differentiation through interaction with cRAF and Trk. Sci Rep. 2013, 3:2397. doi: 10.1038/srep02397

Giralt A., Puigdellivol M., Paoletti P., Carretón O., Valero J., Parra-Damas A., Saura C.A, Alberch J., and Ginés S. Long-term memory deficits in Huntington’s disease are associated with reduced CBP histone acetylase activity. 
Hum Mol Genet
. 2012, 21(6):1203-16.  doi: 10.1093/hmg/ddr552

Barneda-Zahonero B., Servitja J.M., Badiola N., Minano-Molina A.J., Fado R., Saura C.A., Rodriguez-Alvarez J. Nurr1 is required for NMDA receptor-mediated neuronal survival
J Biol Chem
. 2012, 287(14):11351-62 doi: 10.1074/jbc.M111.272427

Saura C.A., Servián E. and Gómez-Scholl F. Presenilin/γ-secretase regulates neurexin processing at synapses. 
PloS One. 
2011, 6(4) e19430. doi: 10.1371/journal.pone.0019430

España J., Valero J., Miñano A., Masgrau R., Martin E., Guardia-Laguarta C., Lleó A., Giménez-Llort L., Rodríguez-Alvarez J. and Saura C.A. β-Amyloid disrupts activity-dependent gene transcription required for memory through the CREB coactivator CRTC1. 
J Neurosci
. 2010, 30(28):9402-10.  doi: 10.1523/JNEUROSCI.2154-10.2010

Novel research tools and models of neurodegeneration

We use pioneering genetic approaches (mouse genetics, gene targeting, optogenetics…) to develop novel research tools and transgenic mouse models for studying gene function and neural circuits in health and brain disorders. These innovative experimental tools and models are useful for testing research hypothesis and new therapeutic strategies for Alzheimer’s disease and related cognitive disorders.

We have recently generated and characterized novel brain- and skin-specific presenilin-1/2 conditional knockout mouse models that are useful to understand the biological and pathological functions of these genes in different tissues.

Vargas-Estevez C, Duch M1, Duque M, Del Campo FJ, Enriquez-Barreto L, Murillo G, Torras N, Plaza JA, Saura CA*, Esteve J* Suspended silicon microphotodiodes for electrochemical and biological applications  
Small
.2017,13(41). doi: 10.1002/smll.201701920

Parra-Damas A., Valero J., Chen M., España J., Martin E., Ferrer I., Rodríguez-Alvarez J. and Saura C.A.  Crtc1 activates a transcriptional program deregulated at early Alzheimer’s disease-related stages 
J Neurosci
. 2014, 34(17):5776-87. Featured cover.  doi: 10.1523/JNEUROSCI.5288-13.2014

Rocher-Ros V., Marco S., Mao J.H., Gines, S., Metzger D., Chambon, P., Balmain A. and Saura C.A.Presenilin modulates EGFR signaling and cell transformation by regulating the ubiquitin ligase Fbw7.
Oncogene.
2010, 29(20):2950-61.  doi: 10.1038/onc.2010.57

Saura C.A., Chen G., Malkani S., Choi S.-Y., Zhang D., Takahashi R.H., Gouras G.K., Kirkwood A., Morris R.G.M. and Shen J. Conditional inactivation of presenilin-1 prevents amyloid accumulation and temporarily rescues associative and working memory impairments in APP transgenic mice.
J Neurosci.
2005, 25(29):6755-64.

Saura C.A., Choi S.-Y., Beglopoulos V., Malkani S., Zhang D., Shankaranarayana Rao B. S., Chattarji S., Kelleher III R. J., Kandel E. R., Duff K., Kirkwood A. and Shen J. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.
Neuron.
2004, 42:23-36.

Saura C.A.*, Yu H.*, Choi S-Y., Sun L.D., Yang X., Handler M., Kawarabayashi T., Younkin L., Fedeles B., Wilson M.A., Younkin S., Kandel E.R., Kirkwood A. and Shen J. APP processing and synaptic plasticity in presenilin-1 conditional.
Neuron. 2001, 31(5):713-726.

Research
Research

Therapies for Alzheimer’s disease and cognitive disorders

The discovery of novel molecular mechanisms underlying synaptic dysfunction and memory loss in transgenic and knockout mouse models of Alzheimer’s disease allow us to design new therapeutic strategies to prevent and/or reverse pathological changes and cognitive dysfunction. Particularly, our aim is to discover biological markers and to develop novel pharmacological, gene therapy and non-invasive treatments that enable to reduce brain pathology and recover brain function during Alzheimer’s disease.

Our lab has recently developed novel gene therapy approaches to ameliorate gene expression changes and cognitive deficits associated with Alzheimer’s disease. We also investigate the cellular mechanisms underlying the beneficial effects of cognitive stimulation on adult neurogenesis and memory in Alzheimer’s disease.

Lopez-Font I., Sogorb-Esteve A., Javier-Torrent M., Brinkmalm G., Herrando-Grabulosa M., García-Lareu B., Turon-Sans J., Rojas-García R., Lleó A., Saura CA., Zetterberg H., Blennow K., Bosch A., Navarro X., Sáez-Valero J. Decreased circulating ErbB4 ectodomains fragments as a read-out of impaired signaling function in amyotrophic lateral sclerosis. 
Neurobiol Disease. 2019, 124:428-438. doi: 10.1016/j.nbd.2018.12.021

Van der Jeugd A., Parra-Damas A., Baeta-Corral R., Soto-Faguás CM., Ahmed T., LaFerla FM., Giménez Llort L., D’Hooge R., Saura C.A Reversal of memory and neuropsychiatric-like symptoms and reduced tau pathology by selenium treatment in 3xTg-AD mice.  
Sci Reports. 2018, 8:6431.doi: 10.1038/s41598-018-24741-0

Parra-Damas A., Chen M., Enríquez-Barreto L., Ortega L., Acosta S., Camats Perna J., Fullana N, Aguilera J., Rodríguez-Alvarez J, and Saura C.A. CRTC1 function during memory encoding is disrupted in neurodegeneration.  
Biological Psychiatry 2017, 81(2):111-123.doi: 10.1016/j.biopsych.2016.06.025

Parra-Damas A., Valero J., Chen M., España J., Martin E., Ferrer I., Rodríguez-Alvarez J. and Saura C.A.  Crtc1 activates a transcriptional program deregulated at early Alzheimer’s disease-related stages 
J Neurosci
. 2014, 34(17):5776-87. Featured cover.  doi: 10.1523/JNEUROSCI.5288-13.2014

Garcia-Ayllón M-S., Campanari M-L., Brinkmalm G., Rábano A., Alom J., Saura C.A., Andreasen N., Blenow K. and Sáez-Valero J. CSF Presenilin-1 complexes are increased in Alzheimer’s disease.
Acta Neuropathol Comm. 2013, 1:46. doi: 10.1186/2051-5960-1-46

Giralt A., Puigdellivol M., Paoletti P., Carretón O., Valero J., Parra-Damas A., Saura C.A, Alberch J., and Ginés S. Long-term memory deficits in Huntington’s disease are associated with reduced CBP histone acetylase activity.
Hum Mol Genet
. 2012, 21(6):1203-16.  doi: 10.1093/hmg/ddr552

España J., Giménez-Llort L., Valero Gómez-Lobo J., Miñano A., Rábano A., Rodríguez-Alvarez J., LaFerla F.M. and Saura C.A.Intraneuronal Aβ accumulation in the amygdala enhances fear and anxiety in Alzheimer’s disease transgenic mice.
Biol Psychiatry. 2010, 67(6):513-521.  doi: 10.1016/j.biopsych.2009.06.015

Valero J., España J., Parra-Damas A., Martin E., Rodríguez-Alvarez J. and Saura C.A. Short-term environmental enrichment rescues adult neurogenesis and memory deficits in APPSw,Ind transgenic mice.
PloS One.
2011, 6(2) e16832. doi: 10.1371/journal.pone.0016832

Coma M., Serenó L., Da Rocha-Souto B., Scotton T.C., España, J., Sánchez M.B., Rodríguez M., Guardia-Laguarta C., Garcia-Alloza M., Borrelli L.A., Clarimón J., Lleó A., Bacskai B.J., Saura C.A., Hyman B.T., Gómez-Isla T.  Triflusal reduces dense-core plaque load, associated axonal alterations and inflammatory changes, and rescues cognition in a transgenic mouse model of Alzheimer’s disease.
Neurobiol Disease 2010, 38(3):482-491  doi: 10.1016/j.nbd.2010.01.019