Amyloidosis and Neurodegeneration

We are studying the basic aspects of the relationship between the accumulation of amyloid proteins and neurodegenerative disorders, including Alzheimer’s disease (AD) and hereditary dementias. We are interested in those mechanisms involved in the accumulation of amyloid peptides (especially amyloid β), particularly in proteases, such as IDE and NEP that degrade them physiologically. It is likely that an increase in the levels of cerebral Aβ and oligomer formation are progressively toxic to different cell types in the CNS along aging. To study early Aβ toxicity we are using transgenic rats (McGil-R-Thy1-APP) and Drosophila transgenic lines designed in our lab for site-directed genome insertion and low expression levels of Aβ and other peptides associated with hereditary dementia. Other recently started lines of research are 1) the study of the effect of oxidative stress upon oligodendrocyte function and 2) the search for genetic polymorphisms that may confer risk for sporadic AD in the argentine population. We also maintain a long-term collaboration with Alex Roher’s lab at Banner Health Research Institute, AZ, to study the biochemistry and protemics in brains of patients with AD.

Study of the regulation of IDE gene expression and its subcellular localization.
Role of mitochondrial Aβ early toxicity in transgenic rats.
Mechanisms of toxicity and screening for modulators in transgenic flies expressing amyloid peptides.
Effects of oxidative stress upon oligodendrocyte function.
Search of genetic polymorphic patterns that contribuye to sporadic AD risk in the argentine population.

Bocai NI, Marcora MS, Belfiori-Carrasco LF, Morelli L, Castaño EM (2018). Endoplasmic reticulum stress in tauopathies: contrasting human brain pathology with cellular and animal models. Journal of Alzheimer's Disease, en revision.

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 (2018). Transethnic meta-analysis of rare coding variants in PLCG2, ABI3, and TREM2 supports their general contribution to Alzheimer’s disease. Translational Psychiatry, en revisión

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. https://doi.org/10.1016/j.celrep.2017.03.034

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. https://doi.org/10.3389/fnagi.2017.00061

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

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

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