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 ONE HEALTH / Noncommunicable chronic diseases / Neurodegenerative diseases

Laboratory of neurobiology and cognition in aging and neurodegenerative diseases

Modulation of inflammatory response and glial reactivity
in neurodegeneration models

Work team

Principal InvestigatorBellini

Bellini, María José

Investigator
mariajosebellini@med.unlp.edu.ar

Sisti, MilagrosSisti

Research Fellow
msisti@med.unlp.edu.ar

Collaborators from other institutions

Arévalo, Angeles
Instituto Cajal, Madrid, España.

Trostchansky, Andrés
Facultad de Medicina-UdelaR- Montevideo-Uruguay.

De Giusti, Verónica Celeste
Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani" –(CIC-FCM-UNLP-CONICET).

Labombarda, Florencia
Instituto de Biología y Medicina Experimental – Consejo Nacional de Investigaciones Científicas y Técnicas - (IBYME -CONICET).

Francini, Flavio
Centro de Endocrinología Experimental y Aplicada -CENEXA- FCM-UNLP-CONICET).

Line overview

Main interests:

Our main interest is focused on elucidate the mechanisms leading to neurodegeneration during aging, basically those related to the inflammatory response.
The essential objective of our work is to develop therapeutic strategies that recover age-affected neuronal populations. The possibility of employing neurotrophic factors that prevent neurodegeneration, increase neuron recovery and regulate inflammatory response is clinically relevant.

Inflammation and Neurodegeneration:

Chronic inflammation, characterized by the activation of microglia and astrocytes, is a hallmark of aging and many neurodegenerative diseases.
Identifying and targeting the triggers of neuroinflammation presents a viable therapeutic strategy.

IGF-I gene therapy and dietary supplementation with omega-3 fatty acids (ω-3) have demonstrated potent anti-inflammatory and neuroprotective properties.

IGF-I is a neurotrophic factor with multiple effects on the central nervous system, exerting a potent anti-inflammatory action. On the other hand, as precursors of resolvins and protectins, ω-3 modulate the inflammatory response and promote its resolution.
These molecules make them promising candidates to modulate neuroinflammation during aging and its negative consequences.

Research objectives:
1. To evaluate the individual and combined effects of IGF-I and ω-3 in animal models of aging and neurodegenerative diseases:
   • To determine if the co-administration of IGF-I and ω-3 potentiates neuroprotective and anti-inflammatory effects.
   • to explore the underlying molecular mechanisms of this synergy.
2. Investigate the role of ω-3 in modulating the microglia and astrocyte-mediated inflammatory response:
   • To evaluate the effects of ω-3 on the expression of inflammatory markers in glial cells.
   • To determine if ω-3 can alter microglia polarization towards an anti-inflammatory phenotype.
3. Characterize changes in the brain lipid profile associated with aging and different treatments:
   • To quantify levels of ω-3, ω-6, and their eicosanoid derivatives in different brain regions.
   • To correlate changes in the lipid profile with inflammation and neurodegeneration parameters.
4. Explore the molecular mechanisms underlying the neuroprotective effects of IGF-I and ω-3:
   • To evaluate the activation of signaling pathways such as PI3K/Akt and MAPK.
   • To analyze the expression of genes related to neuronal survival and neurogenesis.
5. Determine whether sex and aging modulate the response to treatments with IGF-1 and ω-3:
   • To compare the effects of treatments in males and females.
   • To evaluate if age influences the efficacy of combined therapies.

By addressing these objectives, we aim to better understand how the combination of IGF-1 and ω-3 can improve brain health and delay the progression of neurodegenerative diseases.

Lines of work

1-Cell reprogramming and gene therapy for the treatment of motor dopaminergic neurodegeneration.

Principal Investigator: María José Bellini

The ultimate objective of the present project is to study comprehensively the motor-nervous system applying strategies of gene therapy and regenerative medicine in the dopaminergic system (nigro-striatal) in order to improve the age-related deficiencies in the motor pathways of the encephalic dopaminergic system.

2-Hypothalamus as aging regulating center - Anti-inflammatory gene therapy.

Principal Investigator: María José Bellini

The central hypothesis of the present plan is that the transfer of neuroprotective genes constitutes an effective strategy to diminish the inflammatory response in the aging, constituting a possible treatment of diverse age-related neurodegenerative processes. In particular we consider that intrahypothalamic gene therapy for insulin-like growth factor type I (IGF-I) would module the immune response with the subsequent delay in the onset of aging-associated damages and/or their improvement once they have occurred.
Aging is the result of multiple physiological changes, and the hypothalamus can be an underlying mediator representing a target of controlling strategies to counteract aging and aging-related diseases.

3-Effect of omega-3 fatty acids on models of chronic inflammation induced by aging.

Principal Investigator: María Milagros Sisti

Hypothesis:a diet enriched in omega-3 fatty acids (ω-3 FAs), starting from weaning, prevents the development of behavioral disorders in spontaneously aging rats in a sex- and age-dependent manner. The cognitive improvement associated with dietary supplementation with these FAs constitutes a preventive strategy to delay the onset of neurodegenerative pathologies associated with neuroinflammation and aging.

Specific Objectives:
1. Study of lipid composition: To study the total lipid composition and the content of ω-3 FAs in plasma and in brain areas related to behavior and metabolic regulation, such as the cortex, hippocampus, and hypothalamus.
2. Biophysical properties of membranes: To evaluate the biophysical properties (fluidity and lateral organization) of model membranes composed of total lipid extracts from the brains of the experimental animals.
3. Behavioral evaluation: To evaluate behavioral changes, especially cognitive, motor, and anxiety/depression-related behavior.
4. Analysis of lipid mediators: To identify, characterize, and quantify pro-inflammatory, anti-inflammatory, and/or specialized pro-resolving lipid mediators. These will be analyzed in plasma and brain, and correlated with behavior.
5. Study of glial and neuronal response: To study the glial and neuronal response, as well as its correlation with behavior in different brain regions.


IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons.
Dolcetti, Franco Juan Cruz; Falomir-Lockhart, Eugenia; Acuña, Francisco; Herrera, Macarena Lorena; Cervellini, Sofia; Barbeito, Claudio Gustavo; Grassi, Daniela; Arevalo, Mariaangeles; Bellini, María José.
2022. Aging. : Impact journals, 2022 - . vol. 1, p. 8615-8632. ISSN 1945-4589
DOI: 10.18632/aging.204360

IGF-1 Gene Transfer Modifies Inflammatory Environment and Gene Expression in the Caudate-Putamen of Aged Female Rat Brain.
Falomir-Lockhart, Eugenia; Dolcetti, Franco Juan Cruz; Herrera, Macarena Lorena; Pennini, Jerónimo; Zappa Villar, María Florencia; Salinas, Gabriela; Portiansky, Enrique; Spittau, Björn; Lacunza, Ezequiel; Hereñú, Claudia Beatriz; Bellini, María José.
2022. Molecular neurobiology. Oregon: HUMANA PRESS INC. vol. 59, n° 6, p. 3337-3352. ISSN 0893-7648
DOI: 10.1007/s12035-022-02791-w

Intramuscular insulin-like growth factor-1 gene therapy modulates reactive microglia after traumatic brain injury.
Herrera, Macarena Lorena; Bandín, Sandra; Champarini, Leandro Gabriel; Hereñú, Claudia Beatriz; Bellini, Maria Jose.
2021. Brain research bulletin. PERGAMON-ELSEVIER SCIENCE LTD, - vol. 175, p. 196-204. ISSN 0361-9230

IGF1 Gene Therapy Reversed Cognitive Deficits and Restored Hippocampal Alterations After Chronic Spinal Cord Injury.
Jure, Ignacio; Lockhart, Eugenia Falomir; De Nicola, Alejandro F.; Bellini, María Jose; Labombarda, Florencia.
2021. Molecular neurobiology. Oregon: HUMANA PRESS INC,- . vol. 58, n° 12, p. 6186-6202. ISSN 0893-7648

Intracisternal IGF-1 gene therapy abrogates kainic acid-induced excitotoxic damage of the rat spinal cord.
Nishida, Fabián; Zanuzzi, Carolina N. (Idéntica Contribución Con El Primer Autor); Sisti, María S.; Falomir Lockhart, Eugenia; Camiña, Agustina E.; Hereñú, Claudia B.; Bellini, María J.; Portiansky, Enrique L.
2020. European journal of neuroscience. Londres: WILEY-BLACKWELL PUBLISHING, INC, 2020 -. vol. 52, n° 5, p. 3339-3352. ISSN 0953-816X
doi.org/10.1111/ejn.14876

Dancing with Glia: The Role of Astrocytes, Microglia and Oligodendrocytes and their Relation with Neurons in Neuroinflammation and Aging.
Macarena Lorena Herrera; Franco Juan Cruz Dolcetti; Eugenia Falomir-Lockhart; Leandro Champarini; Jeronimo Peninni; Claudia B Hereñú; Maria José Bellini.
2020. Open access journal of biomedical science. Biomedscis, 2020 - vol. 3, p. 732-741
doi.org/10.38125/OAJBS.000238

Modulating Glial Cells Phenotype: New Findings and Therapies.
Bellini, María José; Diz-Chaves, Yolanda; Ramos, Alberto Javier.
2020. Frontiers in aging neuroscience. Frontiers Media S.A., 2020 - . vol. 12
doi.org/10.3389/fnagi.2020.594870

Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?.
Herrera, Macarena L.; Deza-Ponzio, Romina; Ghersi, Marisa S.; De La?Villarmois, Emilce A.; Virgolini, Miriam B.; Pérez, Mariela F.; Molina, Victor A.; Bellini, María J * Corresponding Author, Equally Contribution; Hereñú, Claudia B. * Corresponding Author, Equally Contribution.
2020. Asn neuro. Thousand Oaks: SAGE, 2020 - vol. 12, ISSN 1759-0914
doi.org/10.1177/1759091420925977

Sex frailty differences in ageing mice: Neuropathologies and therapeutic projections.
Herrera, Macarena Lorena; Basmadjian, Osvaldo Martin; Falomir-Lockhart, Eugenia; Dolcetti, Franco Juan?Cruz; Hereñú, Claudia Beatriz * Corresponding Author, Equally Contribution; Bellini, María José * Corresponding Author, Equally Contribution.
2020. European journal of neuroscience. Londres: WILEY-BLACKWELL PUBLISHING, INC, p. 2827-2837. ISSN 0953-816X
doi.org/10.1111/ejn.14703

IGF1 Gene Therapy Modifies Microglia in the Striatum of Senile Rats. Frontiers in aging neuroscience.
Falomir-Lockhart E; Dolcetti, Franco Juan Cruz; García-Segura, Luis M.; Hereñu, Claudia B.; Bellini, Maria J.
2019: Lausanne: Frontiers Research Foundation. ISSN 1663-4365
doi.org/10.3389/fnagi.2019.00048

Novel adenoviral IGF-1 administration modulates the association between depressive symptoms and aging: Does gender matter?
Herrera, Macarena Lorena; Basmadjian, Osvaldo Martín; Falomir Lockhart, Eugenia; Dolcetti, Franco Juan-Cruz; Hereñú, Claudia Beatriz; Bellini, María José.
2019: Behavioural brain research. Amsterdam: ELSEVIER SCIENCE BV, vol. 372, ISSN 0166-4328
doi.org/10.1016/j.bbr.2019.112050

Physical, histological, endocrinological and steroidogenical evaluation of male cats postnatally exposed to sexual steroids.
Grisolia, M.; Faya, M.; Marchetti, C.; Merlo, M. López; D´Francisco, F.; Bellini, M. J.; Gobello, C.
2019: Theriogenology. Amsterdam: ELSEVIER SCIENCE INC, vol. 138, p. 47-51. ISSN 0093-691X
doi.org/10.1016/j.theriogenology.2019.06.041

Estradiol Activates PI3K/Akt/GSK3 Pathway Under Chronic Neurodegenerative Conditions Triggered by Perinatal Asphyxia.
Saraceno, G. E; Bellini, M. J; García-Segura, L. M; Capani, F.
2018. Frontiers in pharmacology. Lausanne: Frontiers Media. vol. 9.
doi.org/10.3389/fphar.2018.00335

Exploring the effects of IGF-1 gene therapy to modulate neuroinflammation.
Falomir-Lockhart, E; Dolcetti, F. J. C; Anesetti-Nelli, S. J; Hereñu, C. B; Bellini, M. J.
2017. Glia: Wiley-Liss, Div John Wiley & Sons Inc. vol. 65, n° S1, p. 90-91. ISSN 0894-1491

Deterioro cognitivo asociado a la patología parkinsoniana: El rol del hipocampo.
Herrera, M. L; Falomir Lockhart, E; Dolcetti, F. J. C; Bellini, M. J; Hereñu, C. B.
2016. Ciencia insitu: Federación Argentina Científica de Estudiantes de la Salud, vol. 1, n° 2, p. 23-27. ISSN 2469-2433

Estrogen actions on glial reactivity and inflammation-mediated memory impairment: Sex differences and interaction with other neurotrophic factors.
Bellini, M. J.
2015. González-Burgos (Ed.); Nova Science Publishers, July 01, 2015, Pages 155-174

Neuroprotective gene therapy in the aging brain.
Pardo, J; Morel, G. R; Pereyra, A. S; López-León, M; Brown-O. A, Bellini, M. J; Goya, R. G.
2014. Estrogens and Cognition. Psycho-biological and Clinical Aspects: González-Burgos (Ed.) ISBN: 978-81-308-0550-4; pp.97-117

Estradiol and testosterone regulate arginine-vasopressin expression in SH-SY5Y human female neuroblastoma cells through estrogen receptors-α and -β.
Grassi, D; Bellini, M. J; Acaz-Fonseca, E; Panzica, G; Garcia-Segura, L. M.
2013. Endocrinology. 154: 2092-100

Prenatal stress increases the expression of proinflammatory cytokines and exacerbates the inflammatory response to LPS in the hippocampal formation of adult male mice.
Diz-Chaves, Y; Astiz, M; Bellini, M. J; Garcia-Segura, L. M.
2013. Brain Behavior and Immunity. Amsterdam: Academic Press Inc Elsevier Science. vol. 28, p. 196-206. ISSN 0889-1591

Influence on Effectiveness of Early Treatment with Anti-TNF Therapy in Rheumatoid Arthritis.
Escudero-Vilaplana, V; Ramírez-Herraiz, E; Trovato-López, N; Alañón-Plaza, E; Bellini, M; Herranzalonso, A; Bellón-Cano, J.M; Morell-Baladrón, A; Sanjurjo-Sáez, M.
2012. Journal of pharmacy and pharmaceutical sciences. : Canadian Soc Pharmaceutical Sciences, vol. 15, n° 3, p. 355-360

Selective oestrogen receptor modulators decrease the inflammatory response of glial cells.
Arevalo, M.A; Diz-Chaves, Y; Santos-Galindo, M; Bellini, M.J; Garcia-Segura, L.M.
2012. Journal of neuroendocrinology. Oxford: Wiley-Blackwell Publishing, Inc, vol. 24, p. 183-190

Increased romatase expression in the hippocampus of spontaneously hypertensive rats: effects of estradiol administration.
Pietranera, L; Bellini, M. J; Arévalo, M. A; Goya, R; Brocca, M. E; García Segura, L. M; De Nicola, A. F.
2011. Neuroscience, 174: p. 151-159

Insulin-like growth factor I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide.
Bellini, M. J; Hereñú, C. B; Goya, R. G; García Segura, L. M.
2011. Neuroinflammation, 8: 21

Glial cell line-derived neurotrophic factor gene therapy ameliorates chronic hyperprolactinemia in senile rats.
Morel, G. R; Sosa, Y. E; Bellini, M. J; Carri, N. G; Rodriguez, S, S; Bohn, M. C; Goya, R.
2010. Neuroscience; vol. 167 p. 946 - 953

Fatty acid profiles in hepatic membranes of rats with different levels of circulating estrogen and prolactin.
Bellini, M. J; Carino, M; Tacconi de Gomez Dumm, I. N; Goya, R. G.
2007. Comparative biochemistry and physiology molecular and integrative physiology. USA: Elsevier. vol. 146, p. 470-474

Implication of oxidative stress, aging and inflammatory processes in neurodegenerative diseases: growth factors as therapeutic approach.
Herrera Macarena Lorena; Falomir-Lockhart, Eugenia; Dolcetti, Franco Juan Cruz; Arnal, Nathalie; Bellini, María Jose; Hereñu, Claudia B.; Disgiulo, Pascual.
2019: Springer, p. 1-465. ISBN 978-3-319-17103-6
10.1007/978-3-319-95360-1_14

Implication of oxidative stress, aging and inflammatory processes in neurodegenerative diseases: growth factors as therapeutic approach.
Herrera, M. L; Falomir-Lockhart, E; Dolcetti, F. J. C; Arnal, N; Bellini, M. J; Hereñu, C. B; Gargiulo, P. A; Mesones Arroyo, H. L.
2018. Springer, p. 165-176. ISBN 978-3-319-95359-5



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