The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain is associated to the cognitive decline of Alzheimer’s disease (AD) patients. To date no resolutive therapies exist. This study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase) and acetylcholine (Ach) release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa) and potassium (IK) currents, as well as the presence of functional cholinergic receptors. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF), through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for neurodegenerative dsorders, such as AD.

Young human cholinergic neurons respond to physiological regulators and improve cognitive symptoms in an animal model of Alzheimer’s disease / Annamaria, Morelli; Erica, Sarchielli; Giulia, Guarnieri; Elisabetta, Coppi; Daniela, Pantano; Paolo, Comeglio; Pamela, Nardiello; Pugliese, Anna M.; Lara, Ballerini; Rosanna, Matucci; Stefano, Ambrosini; Giuseppe, Castronovo; Rosa, Valente; Benedetta, Mazzanti; Sandra, Bucciantini; Mario, Maggi; Fiorella, Casamenti; Pasquale, Gallina; Gabriella B., Vannelli. - In: FRONTIERS IN CELLULAR NEUROSCIENCE. - ISSN 1662-5102. - ELETTRONICO. - 11:339:(2017), pp. 1-17. [10.3389/fncel.2017.00339]

Young human cholinergic neurons respond to physiological regulators and improve cognitive symptoms in an animal model of Alzheimer’s disease

Annamaria Morelli
;
Erica Sarchielli;Giulia Guarnieri;Elisabetta Coppi;Daniela Pantano;Paolo Comeglio;Pamela Nardiello;Anna M. Pugliese;Lara Ballerini;Rosanna Matucci;Stefano Ambrosini;Giuseppe Castronovo;Benedetta Mazzanti;Mario Maggi;Fiorella Casamenti;Pasquale Gallina;Gabriella B. Vannelli
2017

Abstract

The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain is associated to the cognitive decline of Alzheimer’s disease (AD) patients. To date no resolutive therapies exist. This study is aimed at isolating cholinergic neurons from the human fetal NBM (hfNBMs) in order to study their phenotypic, maturational and functional properties. Extensive characterization confirmed the cholinergic identity of hfNBMs, including positivity for specific markers (such as choline acetyltransferase) and acetylcholine (Ach) release. Electrophysiological measurements provided the functional validation of hfNBM cells, which exhibited the activation of peculiar sodium (INa) and potassium (IK) currents, as well as the presence of functional cholinergic receptors. The hfNBMs cholinergic phenotype was regulated by the nerve growth factor (NGF), through the activation of the high-affinity NGF receptor TrkA, as well as by 17-β-estradiol through a peculiar recruitment of its own receptors. When intravenously administered in NBM-lesioned rats, hfNBMs determined a significant improvement in memory functions. Histological examination of brain sections showed that hfNBMs reached the damaged brain areas. The study provides a useful model to study the ontogenetic mechanisms regulating the development and maintenance of the human brain cholinergic system and to assess new lines of research, including disease modeling, drug discovery and cell-based therapy for neurodegenerative dsorders, such as AD.
2017
11:339
1
17
Goal 3: Good health and well-being for people
Annamaria, Morelli; Erica, Sarchielli; Giulia, Guarnieri; Elisabetta, Coppi; Daniela, Pantano; Paolo, Comeglio; Pamela, Nardiello; Pugliese, Anna M.; Lara, Ballerini; Rosanna, Matucci; Stefano, Ambrosini; Giuseppe, Castronovo; Rosa, Valente; Benedetta, Mazzanti; Sandra, Bucciantini; Mario, Maggi; Fiorella, Casamenti; Pasquale, Gallina; Gabriella B., Vannelli
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1105767
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