Envejecimiento cerebral y Neurodegeneración

Eduardo Castaño - Fundación Instituto Leloir

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Nuestros intereses principales son:
  1. Comprender cuál es la relación entre las enfermedades neurodegenerativas (especialmente Alzheimer) y la acumulación en el cerebro de proteínas anormales llamadas amiloides.
  2. Dilucidar los mecanismos moleculares involucrados en la disfunción bioenergética cerebral asociada al depósito de proteínas amiloides (en especial amiloide β, Aβ).
  3. Definir en población argentina marcadores genéticos y otros biomarcadores que en conjunto puedan contribuir a un mayor riesgo de padecer Alzheimer.
Para el estudio de la toxicidad de Aβ en estadios tempranos utilizamos como modelos animales ratas transgénicas (McGill-R-Thy1-APP) y líneas transgénicas de Drosophila melanogaster diseñadas para inserción sitio-dirigida de péptidos amiloides asociados a demencias (Alzheimer y demencias familiares Danesa y Británica). Con estos modelos evaluamos comportamiento (ratas y moscas) y disecamos mecanismos moleculares utilizando cultivos celulares de neuronas y células de la glía. Analizamos muestras humanas (sangre, saliva, cerebro post-mortem) para validación de biomarcadores.

  • Modulación de la toxicidad y acumulación de amiloide mediante screening genético en el SNC de Drosophila
  • Estudio de los Super-Complejos mitocondriales en cerebro de ratas transgénicas McGill-R-Thy1-APP
  • Impacto de la dieta, la microbiota y la neuroinflamación en la progresión del Alzheimer (estudios preclínicos y en humanos)
  • Selección de marcadores genéticos en población Argentina y desarrollo de un algoritmo predictivo. Búsqueda de biomarcadores.

Martino Adami PV, Nichtová Z, Weaver DB, Bartok A, Wisniewski T, Jones DR, Do Carmo S, Castaño EM, Cuello AC, Hajnóczky G, Morelli L (2019). Perturbed mitochondria-ER contacts in live neurons modelling Alzheimer's disease amyloid pathology. Journal of Cell Science, in press. https://doi.org/10.1242/jcs.229906

Martino Adami PV, Nichtová Z, Weaver DB, Bartok A, Wisniewski T, Jones DR, Do Carmo S, Castaño EM, Cuello AC, Hajnóczky G, Morelli L (2019). Perturbed mitochondria-ER contacts in live neurons modelling Alzheimer's disease amyloid pathology. Journal of Cell Science, in press. https://doi.org/10.1242/jcs.229906

Bocai NI, Marcora MS, Belfiori-Carrasco LF, Morelli L, Castaño EM (2019). Endoplasmic reticulum stress in tauopathies: contrasting human brain pathology with cellular and animal models. Journal of Alzheimer's Disease,  68, 439-458. https://doi.org/10.3233/JAD-181021

Dalmasso MC, Brusco LI, Olivar N, Muchnik C, Hanses C, Milz E, Becker J, Heilmann-Heimbach S, Hoffmann P, Prestia FA, Galeano P, Sanchez Avalos MS, Martinez LE, Carulla ME, Azurmendi PJ, Liberczuk C, Fezza C, Sampaño M, Fierens M, Jemar G, Solis P, Medel N, Lisso J, Sevillano Z, Bosco P, Bossù P, Spalletta G, Galimberti D, Mancuso M, Nacmias B, Sorbi S, Mecocci P, Pilotto A, Caffarra P, Panza F, Bullido M, Clarimon J, Sánchez-Juan P, Alvarez V, Coto E, Sanchez-Garcia F, Graff C, Ingelsson M, Bellenguez C, Castaño EM, Kairiyama C, Politis DG, Kochen S, Scaro H, Maier W, Jessen F, Mangone CA, Lambert J-C, Morelli L, Ramirez A (2019). Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease. Translational Psychiatry, 9, 55. https://doi.org/10.1038/s41398-019-0394-9    

Prestia FA, Galeano P, Martino Adami PV, Do Carmo S, Castaño EM, Cuello AC, Morelli L (2018). Platelets bioenergetics screening reflects the impact of brain Aβ plaque accumulation in a rat model of Alzheimer. Neurochemical Research, en prensa. PubMed

Galeano P, Leal MC, Ferrari CC, Dalmasso MC, Martino Adami PV, Farías MI, Casabona JC, Puntel M, Do Carmo S, Smal C, Arán M, Castaño EM, Pitossi FJ, Cuello AC, Morelli L (2018). Chronic hippocampal expression of Notch intracellular domain induces vascular thickening, reduces glucose availability, and exacerbates spatial memory deficits in a rat model of early Alzheimer. Molecular Neurobiology 55, 8637-8650.PubMed

Marcora MS, Belfiori-Carrasco LF, Bocai NI, Morelli L, Castaño EM (2017). Amyloid-β42 clearance and neuroprotection mediated by X-box binding protein 1 signaling decline with aging in the Drosophila brain. Neurobiology of Aging 60, 57-70. PubMed

Frenkel L, Muraro NI, Beltrán González AN, Marcora MS, Bernabó G, Hermann-Luibl C, Romero JI, Helfrich-Förster C, Castaño EM, Marino-Busjle C, Calvo DJ, Ceriani MF (2017). Organization of circadian behavior relies on glycinergic transmission. Cell Reports 19, 72-85. PubMed

Belfiori-Carrasco LF, Marcora MS, Bocai NI, Ceriani MF, Morelli L, Castaño EM (2017). A novel genetic screen identifies modifiers of age-dependent amyloid β toxicity in the drosophila brain. Frontiers in Aging Neuroscience 9, 61. PubMed

Castelletto V, Ryumin P, Cramer R, Hamley IW, Taylor M, Allsop D, Reza M, Ruokolainen J, Arnold T, Hermida-Merino D, Garcia CI, Leal MC, Castaño E (2017). Self-assembly and anti-amyloid cytotoxicity activity of amyloid beta peptide derivatives. Scientific Reports 7, 43637. PubMed

Martino Adami PV, Galeano P, Wallinger ML, Quijano C, Rabossi A, Pagano ES, Olivar N, Reyes Toso C, Cardinali D, Brusco LI, Do Carmo S, Radi R, Gevorkian G, Castaño EM, Cuello AC, Morelli L (2017). Worsening of memory deficit induced by energy-dense diet in a rat model of early-Alzheimer's disease is associated to neurotoxic Aβ species and independent of neuroinflammation. Biochimica et Biophysica Acta - Molecular Basis of Disease 1863, 731-743.PubMed

Martino Adami PV, Quijano C, Magnani N, Galeano P, Evelson P, Cassina A, Do Carmo S, Leal MC, Castaño EM, Cuello AC, Morelli L (2017). Synaptosomal bioenergetic defects are associated with cognitive impairment in a transgenic rat model of early Alzheimer's disease. Journal of Cerebral Blood Flow and Metabolism 37, 69-84. PubMed

Morelli, L (2016). La contribución de la hipótesis amiloide a la comprensión de la enfermedad de Alzheimer: una visión crítica. Química Viva 15, 7-12.

Martinez-Vivot R, Copello G, Leal MC, Piñero G, Usach V, Rozenszajn M, Morelli L, Setton-Avruj CP (2015). DMT1 iron uptake in the PNS: bridging the gap between injury and regeneration. Metallomics 7, 1381-1389. PubMed

Muchnik C, Olivar N, Dalmasso MC, Azurmendi PJ, Liberczuk C, Morelli L, Brusco LI (2015). Identification of PSEN2 mutation p.N141I in Argentine pedigrees with early-onset familial Alzheimer's disease. Neurobiology of Aging 36, 2674-2677. PubMed

Depetris-Chauvin A, Fernández-Gamba A, Gorostiza EA, Herrero A, Castaño EM, Ceriani MF (2014). Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons. PLoS Genetics 10, e1004700. PubMed

Galeano P, Martino Adami PV, Do Carmo S, Blanco E, Rotondaro C, Capani F, Castaño EM, Cuello AC, Morelli L (2014). Longitudinal analysis of the behavioral phenotype in a novel transgenic rat model of early stages of Alzheimer's disease. Frontiers in Behavioral Neuroscience 8, 321. PubMed

Marcora MS, Fernández-Gamba AC, Avendaño LA, Rotondaro C, Podhajcer OL, Vidal R, Morelli L, Ceriani MF, Castaño EM (2014). Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia. Molecular Neurodegeneration 9, 5. PubMed

Morgenstern NA, Giacomini D, Lombardi G, Castaño EM, Schinder AF (2013). Delayed dendritic development in newly generated dentate granule cells by cell-autonomous expression of the amyloid precursor protein. Molecular and Cellular Neuroscience 56, 298-306. PubMed

Leal MC, Magnani N, Villordo S, Buslje CM, Evelson P, Castaño EM, Morelli L (2013). Transcriptional regulation of insulin-degrading enzyme modulates mitochondrial amyloid β (Aβ) peptide catabolism and functionality. Journal of Biological Chemistry 288, 12920-12931. PubMed

de Tullio MB, Castelletto V, Hamley IW, Martino Adami PV, Morelli L, Castaño EM (2013). Proteolytically inactive insulin-degrading enzyme inhibits amyloid formation yielding non-neurotoxic aβ peptide aggregates. PLoS One 8, e59113. PubMed

Castaño EM, Maarouf CL, Wu T, Leal MC, Whiteside CM, Lue LF, Kokjohn TA, Sabbagh MN, Beach TG, Roher AE (2013). Alzheimer disease periventricular white matter lesions exhibit specific proteomic profile alterations. Neurochemistry International 62, 145-156. PubMed

Mathieu P, Martino Adami PV, Morelli L (2013). Notch signaling in the pathologic adult brain. Biomolecular Concepts 4, 1-12. PubMed





Eduardo Castaño
Jefe de Laboratorio - ecastano@leloir.org.ar
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Laura Morelli
Investigadora Principal CONICET. - lmorelli@leloir.org.ar
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Pablo Galeano
Investigador Adjunto, CONICET
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Lautaro Belfiori Carrasco
Becario Doctoral ANPCyT
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Federico Ariel Prestía
Becario Doctoral, ANPCyT
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Gisela Novack
Becaria Doctoral - CONICET
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