title: The recombinant C-terminal fragment of tetanus toxin protects against cholinotoxicity by intraseptal injection of β-amyloid peptide (25-35) in rats.
abstract: The recombinant C-terminal domain of tetanus toxin (Hc-TeTx) is a new non-toxic peptide of the tetanus toxin that exerts a protective action against glutamate excitotoxicity in motoneurons. Moreover, its efficacy as a neuroprotective agent has been demonstrated in several animal models of neurodegeneration. The eleven amino acids in the β amyloid peptide (Aβ25-35) mimic the toxic effects of the full β amyloid peptide (Aβ1-42), causing the impairment of the cholinergic system in the medial septum (MS) which, in turn, alters the septo-hippocampal pathway and leads to learning and memory impairments. The aim of this study was to examine the neuroprotective effects of the Hc-TeTx fragment against cholinotoxicity. The Hc-TeTx fragment (100 ng) was injected into the rats intercranially, with the Aβ(25-35) (2 μg) then injected into their MS. The animals were tested for spatial learning and memory in the eight-arm radial maze. The brains were removed to assess cholinergic markers, such as choline acetyltransferase (ChAT) and acetylcholinesterase (AChE), and to explore neurodegeneration in the MS and hippocampus, using amino-cupric silver and H&E staining. Finally, capase-3, a marker of apoptosis, was examined in the MS. Our results clearly demonstrate that the application of Hc-TeTx prevents the loss of cholinergic markers (ChAT and AChE), the activation of capase-3, and neurodegeneration in the MS and the CA1 and CA3 subfields of the hippocampus. All these improvements were reflected in spatial learning and memory performance, and were significantly higher compared with animals treated with Aβ(25-35). Interestingly, the single administration of Hc-TeTx into the MS modified the ChAT and AChE expression that affect cognitive processes, without inducing neurodegeneration or an increase in capase-3 expression in the MS and hippocampus. In summary, our findings suggest that the recombinant Hc-TeTx fragment offers effective protection for the septo-hippocampal pathway, given that it reduces the neurodegeneration caused by Aβ(25-35) and improves learning and memory processes.
authors.affiliation: Laboratorio de Neurofarmacología, FCQ-Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: A
authors.initials: A
authors.lastname: Patricio-Martínez
authors.affiliation: Laboratorio de Neurofarmacología, FCQ-Benemérita Universidad Autónoma de Puebla, Puebla, Mexico; Cajal Institute, CSIC, Madrid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Mendieta
authors.affiliation: Laboratorio de Neurofarmacología, FCQ-Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
authors.forename: I
authors.initials: I
authors.lastname: Martínez
authors.affiliation: Departament de Bioquímica i de Biologia Molecular, Facultad de Medicina, Institut de Neurociències, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Aguilera
authors.affiliation: Laboratorio de Neurofarmacología, FCQ-Benemérita Universidad Autónoma de Puebla, Puebla, Mexico. Electronic address: ilhlimon@yahoo.com.mx.
authors.forename: I D
authors.initials: ID
authors.lastname: Limón
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D053148:Caspase 3 / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity; D011897:Random Allocation; D017208:Rats, Wistar; D020665:Septum of Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D013744:Tetanus Toxin / Q000494:pharmacology*
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D010446:Peptide Fragments; D013744:Tetanus Toxin; C074636:amyloid beta-protein (25-35); D002795:Choline O-Acetyltransferase; D000110:Acetylcholinesterase; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: Hc-TeTx; acetylcholinesterase; amyloid-β((25–35)); choline acetyltransferase; medial septum; spatial memory