title: Low-Affinity Neurotrophin Receptor p75 Promotes the Transduction of Targeted Lentiviral Vectors to Cholinergic Neurons of Rat Basal Forebrain.
abstract: Basal forebrain cholinergic neurons (BFCNs) are one of the most affected neuronal types in Alzheimer's disease (AD), with their extensive loss documented at late stages of the pathology. While discriminatory provision of neuroprotective agents and trophic factors to these cells is thought to be of substantial therapeutic potential, the intricate topography and structure of the forebrain cholinergic system imposes a major challenge. To overcome this, we took advantage of the physiological enrichment of BFCNs with a low-affinity p75 neurotrophin receptor (p75NTR) for their targeting by lentiviral vectors within the intact brain of adult rat. Herein, a method is described that affords selective and effective transduction of BFCNs with a green fluorescence protein (GFP) reporter, which combines streptavidin-biotin technology with anti-p75NTRantibody-coated lentiviral vectors. Specific GFP expression in cholinergic neurons was attained in the medial septum and nuclei of the diagonal band Broca after a single intraventricular administration of such targeted vectors. Bioelectrical activity of GFP-labeled neurons was proven to be unchanged. Thus, proof of principle is obtained for the utility of the low-affinity p75NTRfor targeted transduction of vectors to BFCNs in vivo.
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland.
authors.forename: Inga
authors.initials: I
authors.lastname: Antyborzec
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland.|Institute of Radiation Biology, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Leary
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland.
authors.forename: James O
authors.initials: JO
authors.lastname: Dolly
authors.affiliation: International Centre for Neurotherapeutics, Dublin City University, Dublin, Ireland. saak.ovsepian@gmail.com.|Institute for Biological and Medical Imaging, Helmholtz Zentrum Munich, German Research Center for Environmental Health, Neuherberg, Germany. saak.ovsepian@gmail.com.|Munich School of Bioengineering, Technical University Munich, Munich, Germany. saak.ovsepian@gmail.com.
authors.forename: Saak V
authors.initials: SV
authors.lastname: Ovsepian
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D066187:Basal Forebrain / Q000166:cytology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism* / Q000502:physiology; D005260:Female; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D016086:Lentivirus / Q000235:genetics; D008297:Male; D018613:Microscopy, Confocal; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D020800:Receptor, Nerve Growth Factor; D049452:Green Fluorescent Proteins; D002795:Choline O-Acetyltransferase
keywords: Alzheimer’s disease; Basal forebrain cholinergic neurons; Gene therapy; Neuroprotection; Streptavidin–biotin; p75 neurotrophin receptor