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      Young Human Cholinergic Neurons Respond to Physiological Regulators and Improve Cognitive Symptoms in an Animal Model of Alzheimer’s Disease

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          The degeneration of cholinergic neurons of the nucleus basalis of Meynert (NBM) in the basal forebrain (BF) is associated to the cognitive decline of Alzheimer’s disease (AD) patients. To date no resolutive therapies exist. Cell-based replacement therapy is a strategy currently under consideration, although the mechanisms underlying the generation of stem cell-derived NBM cholinergic neurons able of functional integration remain to be clarified. Since fetal brain is an optimal source of neuronal cells committed towards a specific phenotype, 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 (I Na) and potassium (I K) currents, as well as the presence of functional cholinergic receptors. Accordingly, hfNBMs express both nicotinic and muscarinic receptors, which were activated by Ach. 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 (labeled with PKH26 fluorescent dye prior to administration) 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 AD.

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          Most cited references 57

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          A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease.

          Cholinergic neuron loss is a cardinal feature of Alzheimer disease. Nerve growth factor (NGF) stimulates cholinergic function, improves memory and prevents cholinergic degeneration in animal models of injury, amyloid overexpression and aging. We performed a phase 1 trial of ex vivo NGF gene delivery in eight individuals with mild Alzheimer disease, implanting autologous fibroblasts genetically modified to express human NGF into the forebrain. After mean follow-up of 22 months in six subjects, no long-term adverse effects of NGF occurred. Evaluation of the Mini-Mental Status Examination and Alzheimer Disease Assessment Scale-Cognitive subcomponent suggested improvement in the rate of cognitive decline. Serial PET scans showed significant (P < 0.05) increases in cortical 18-fluorodeoxyglucose after treatment. Brain autopsy from one subject suggested robust growth responses to NGF. Additional clinical trials of NGF for Alzheimer disease are warranted.
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            Fate mapping Nkx2.1-lineage cells in the mouse telencephalon.

            The homeodomain transcription factor Nkx2.1 is expressed in the pallidal (subcortical) telencephalon, including the medial ganglionic eminence (MGE) and preoptic area. Studies have shown that Nkx2.1 is required for normal patterning of the MGE and for the specification of the parvalbumin (PV)- and somatostatin (SST)-expressing cortical interneurons. To define the contribution of Nkx2.1 lineages to neurons in the mature telencephalon, we have generated transgenic mice carrying the genomic integration of a modified bacterial artificial chromosome (BAC) in which the second exon of Nkx2.1 is replaced by the Cre recombinase. Analysis of these mice has found that they express the Cre recombinase and Cre reporters within Nkx2.1-expressing domains of the brain, thyroid, pituitary, and lung. Telencephalic expression of reporters begins at about embryonic day 10.5. Expression both of Cre and of recombination-based Cre reporters is weaker within the dorsalmost region of the MGE than in other Nkx2.1-expressing regions. In this paper, we present fate-mapping data on Nkx2.1-lineage neurons throughout the telencephalon, including the cerebral cortex, amygdala, olfactory bulb, striatum, globus pallidus, septum, and nucleus basalis. Copyright 2007 Wiley-Liss, Inc.
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                Author and article information

                Front Cell Neurosci
                Front Cell Neurosci
                Front. Cell. Neurosci.
                Frontiers in Cellular Neuroscience
                Frontiers Media S.A.
                27 October 2017
                : 11
                1Section of Human Anatomy and Histology, Department of Experimental and Clinical Medicine, University of Florence , Florence, Italy
                2Department of Neuroscience, Psychology, Drug Research and Child Health, Division of Pharmacology and Toxicology, University of Florence , Florence, Italy
                3Sexual Medicine and Andrology Unit, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence , Florence, Italy
                4Cell Therapy and Transfusion Medicine Unit, Department of Experimental and Clinical Medicine, University of Florence , Florence, Italy
                5Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, Section of Clinical Physiopathology , Florence, Italy
                6Careggi University Hospital , Florence, Italy
                7Neurosurgery School of Tuscany, Department of Surgery and Translational Medicine, University of Florence , Florence, Italy
                Author notes

                Edited by: Andrea Nistri, Scuola Internazionale di Studi Superiori Avanzati (SISSA), Italy

                Reviewed by: Nicola Berretta, Fondazione Santa Lucia (IRCCS), Italy; Rory McQuiston, Virginia Commonwealth University, United States

                *Correspondence: Annamaria Morelli a.morelli@ 123456unifi.it
                Copyright © 2017 Morelli, Sarchielli, Guarnieri, Coppi, Pantano, Comeglio, Nardiello, Pugliese, Ballerini, Matucci, Ambrosini, Castronovo, Valente, Mazzanti, Bucciantini, Maggi, Casamenti, Gallina and Vannelli.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 6, Tables: 2, Equations: 0, References: 65, Pages: 17, Words: 13034
                Original Research


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