Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease
Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are n...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2017-12-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996117302097 |
| _version_ | 1818676084475953152 |
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| author | M. Florencia Iulita M. Beatriz Bistué Millón Rowan Pentz Lisi Flores Aguilar Sonia Do Carmo Simon Allard Bernadeta Michalski Edward N. Wilson Adriana Ducatenzeiler Martin A. Bruno Margaret Fahnestock A. Claudio Cuello |
| author_facet | M. Florencia Iulita M. Beatriz Bistué Millón Rowan Pentz Lisi Flores Aguilar Sonia Do Carmo Simon Allard Bernadeta Michalski Edward N. Wilson Adriana Ducatenzeiler Martin A. Bruno Margaret Fahnestock A. Claudio Cuello |
| author_sort | M. Florencia Iulita |
| collection | DOAJ |
| description | Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest. |
| first_indexed | 2024-12-17T08:37:51Z |
| format | Article |
| id | doaj.art-6c0c94eebe334f3fa038f02a235a8d3c |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T08:37:51Z |
| publishDate | 2017-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-6c0c94eebe334f3fa038f02a235a8d3c2022-12-21T21:56:26ZengElsevierNeurobiology of Disease1095-953X2017-12-01108307323Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's diseaseM. Florencia Iulita0M. Beatriz Bistué Millón1Rowan Pentz2Lisi Flores Aguilar3Sonia Do Carmo4Simon Allard5Bernadeta Michalski6Edward N. Wilson7Adriana Ducatenzeiler8Martin A. Bruno9Margaret Fahnestock10A. Claudio Cuello11Department of Pharmacology and Therapeutics, McGill University, Montreal, CanadaFacultad de Ciencias Médicas, Universidad Católica de Cuyo-CONICET, San Juan, ArgentinaDepartment of Neurology and Neurosurgery, McGill University, Montreal, CanadaDepartment of Anatomy and Cell Biology, McGill University, Montreal, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, CanadaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, CanadaDepartment of Neurology and Neurosurgery, McGill University, Montreal, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, CanadaFacultad de Ciencias Médicas, Universidad Católica de Cuyo-CONICET, San Juan, ArgentinaDepartment of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, CanadaDepartment of Pharmacology and Therapeutics, McGill University, Montreal, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada; Department of Anatomy and Cell Biology, McGill University, Montreal, Canada; Corresponding author at: Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, 3655 Sir-William-Osler Promenade, Room 1210, Montreal, QC H3G 1Y6, Canada.Evidence from human neuropathological studies indicates that the levels of the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are compromised in Alzheimer's disease. However, the causes and temporal (pathology-dependent) evolution of these alterations are not completely understood. To elucidate these issues, we investigated the McGill-R-Thy1-APP transgenic rat, which exhibits progressive intracellular and extracellular amyloid-beta (Aβ) pathology and ensuing cognitive deficits. Neurochemical analyses revealed a differential dysregulation of NGF and BDNF transcripts and protein expression. While BDNF mRNA levels were significantly reduced at very early stages of amyloid pathology, before plaques appeared, there were no changes in NGF mRNA expression even at advanced stages. Paradoxically, the protein levels of the NGF precursor were increased. These changes in neurotrophin expression are identical to those seen during the progression of Alzheimer's disease. At advanced pathological stages, deficits in the protease cascade controlling the maturation and degradation of NGF were evident in McGill transgenic rats, in line with the paradoxical upregulation of proNGF, as seen in Alzheimer's disease, in the absence of changes in NGF mRNA. The compromise in NGF metabolism and BDNF levels was accompanied by downregulation of cortical cholinergic synapses; strengthening the evidence that neurotrophin dysregulation affects cholinergic synapses and synaptic plasticity. Our findings suggest a differential temporal deregulation of NGF and BDNF neurotrophins, whereby deficits in BDNF mRNA appear at early stages of intraneuronal Aβ pathology, before alterations in NGF metabolism and cholinergic synapse loss manifest.http://www.sciencedirect.com/science/article/pii/S0969996117302097Alzheimer's diseaseAmyloid-βCholinergicNerve growth factorproNGFBDNF |
| spellingShingle | M. Florencia Iulita M. Beatriz Bistué Millón Rowan Pentz Lisi Flores Aguilar Sonia Do Carmo Simon Allard Bernadeta Michalski Edward N. Wilson Adriana Ducatenzeiler Martin A. Bruno Margaret Fahnestock A. Claudio Cuello Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease Neurobiology of Disease Alzheimer's disease Amyloid-β Cholinergic Nerve growth factor proNGF BDNF |
| title | Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease |
| title_full | Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease |
| title_fullStr | Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease |
| title_full_unstemmed | Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease |
| title_short | Differential deregulation of NGF and BDNF neurotrophins in a transgenic rat model of Alzheimer's disease |
| title_sort | differential deregulation of ngf and bdnf neurotrophins in a transgenic rat model of alzheimer s disease |
| topic | Alzheimer's disease Amyloid-β Cholinergic Nerve growth factor proNGF BDNF |
| url | http://www.sciencedirect.com/science/article/pii/S0969996117302097 |
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