Nerve growth factor metabolic dysfunction in Down’s syndrome brains
Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syn...
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| Published in | Brain (London, England : 1878) Vol. 137; no. 3; pp. 860 - 872 |
|---|---|
| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Oxford
Oxford University Press
01.03.2014
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 0006-8950 1460-2156 1460-2156 |
| DOI | 10.1093/brain/awt372 |
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| Abstract | Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome. |
|---|---|
| AbstractList | Individuals with Down’s syndrome are at increased risk of Alzheimer’s disease. Using post-mortem human brain tissue, foetal cortex cultures and Ts65Dn trisomic mice, Iulita
et al.
reveal marked alterations in nerve growth factor metabolism in Down’s syndrome, consistent with similar defects previously reported by this group in Alzheimer’s disease.
Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer’s disease and Down’s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer’s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF’s extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down’s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (
n
= 14), frontal (
n
= 34) and parietal (
n
= 20) cortex obtained from subjects with Down’s syndrome and age-matched controls (age range 31–68 years). We further examined primary cultures of human foetal Down’s syndrome cortex (17–21 gestational age weeks) and brains from Ts65Dn mice (12–22 months), a widely used animal model of Down’s syndrome. We report a significant increase in proNGF levels in human and mouse Down’s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down’s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down’s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down’s syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer’s disease and Down’s syndrome. Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome. Individuals with Down's syndrome are at increased risk of Alzheimer's disease. Using post-mortem human brain tissue, foetal cortex cultures and Ts65Dn trisomic mice, Iulita et al. reveal marked alterations in nerve growth factor metabolism in Down's syndrome, consistent with similar defects previously reported by this group in Alzheimer's disease. Individuals with Down's syndrome are at increased risk of Alzheimer's disease. Using post-mortem human brain tissue, foetal cortex cultures and Ts65Dn trisomic mice, Iulita et al. reveal marked alterations in nerve growth factor metabolism in Down's syndrome, consistent with similar defects previously reported by this group in Alzheimer's disease. Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome.Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer's disease and Down's syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer's disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor, proNGF. We have shown that this phenomenon is the result of a deficit in NGF's extracellular metabolism that compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down's syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from subjects with Down's syndrome and age-matched controls (age range 31-68 years). We further examined primary cultures of human foetal Down's syndrome cortex (17-21 gestational age weeks) and brains from Ts65Dn mice (12-22 months), a widely used animal model of Down's syndrome. We report a significant increase in proNGF levels in human and mouse Down's syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator messenger RNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Human Down's syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in NGF precursor maturation in Down's syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down's syndrome foetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer's disease and Down's syndrome. |
| Author | Wisniewski, Thomas Busciglio, Jorge Do Carmo, Sonia Iulita, M. Florencia Ower, Alison K. Cuello, A. Claudio Hanna, Michael Fortress, Ashley M. Aguilar, Lisi Flores Granholm, Ann-Charlotte Buhusi, Mona |
| AuthorAffiliation | 2 Department of Neurosciences and the Centre on Ageing, Medical University of South Carolina, BSB Room 403, 173 Ashley Avenue, Charleston, 29425, USA 3 Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, H3G1Y6, Canada 1 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Montreal, H3G1Y6, Canada 4 Department of Neurobiology and Behaviour, University of California, 2205 McGaugh Hall, Irvine, 92697, USA 5 Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, 240 East 38th Street, New York, 10016, USA 6 Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, H3G1Y6, Canada |
| AuthorAffiliation_xml | – name: 1 Department of Pharmacology and Therapeutics, McGill University, 3655 Sir-William-Osler Promenade, Montreal, H3G1Y6, Canada – name: 4 Department of Neurobiology and Behaviour, University of California, 2205 McGaugh Hall, Irvine, 92697, USA – name: 5 Departments of Neurology, Pathology and Psychiatry, New York University School of Medicine, 240 East 38th Street, New York, 10016, USA – name: 3 Department of Anatomy and Cell Biology, McGill University, 3640 University Street, Montreal, H3G1Y6, Canada – name: 2 Department of Neurosciences and the Centre on Ageing, Medical University of South Carolina, BSB Room 403, 173 Ashley Avenue, Charleston, 29425, USA – name: 6 Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, H3G1Y6, Canada |
| Author_xml | – sequence: 1 givenname: M. Florencia surname: Iulita fullname: Iulita, M. Florencia – sequence: 2 givenname: Sonia surname: Do Carmo fullname: Do Carmo, Sonia – sequence: 3 givenname: Alison K. surname: Ower fullname: Ower, Alison K. – sequence: 4 givenname: Ashley M. surname: Fortress fullname: Fortress, Ashley M. – sequence: 5 givenname: Lisi Flores surname: Aguilar fullname: Aguilar, Lisi Flores – sequence: 6 givenname: Michael surname: Hanna fullname: Hanna, Michael – sequence: 7 givenname: Thomas surname: Wisniewski fullname: Wisniewski, Thomas – sequence: 8 givenname: Ann-Charlotte surname: Granholm fullname: Granholm, Ann-Charlotte – sequence: 9 givenname: Mona surname: Buhusi fullname: Buhusi, Mona – sequence: 10 givenname: Jorge surname: Busciglio fullname: Busciglio, Jorge – sequence: 11 givenname: A. Claudio surname: Cuello fullname: Cuello, A. Claudio |
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| Keywords | Chromosomal aberration Endocrinopathy Cholinergic neuron Trisomy Alzheimer disease Central nervous system Aneuploidy Cardiovascular disease Nerve growth factor Metabolic syndrome Encephalon Down's syndrome basal forebrain cholinergic neurons Degenerative disease Alzheimer's disease Nervous system diseases Enzyme Chromosome G21 Metabolic diseases matrix metallo-protease 9 Down syndrome Cerebral disorder Peptidases Metabolic disorder Central nervous system disease proNGF Hydrolases Down’s syndrome Alzheimer’s disease |
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| Snippet | Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on NGF for its synaptic integrity and the phenotypic... Individuals with Down's syndrome are at increased risk of Alzheimer's disease. Using post-mortem human brain tissue, foetal cortex cultures and Ts65Dn trisomic... Individuals with Down’s syndrome are at increased risk of Alzheimer’s disease. Using post-mortem human brain tissue, foetal cortex cultures and Ts65Dn trisomic... |
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| SubjectTerms | Adult Adult and adolescent clinical studies Aged Alzheimer's disease Animals Biological and medical sciences Case-Control Studies Chromosome aberrations Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases Disease Models, Animal Down Syndrome - enzymology Down Syndrome - metabolism Down Syndrome - physiopathology Fetus - enzymology Fetus - metabolism Fetus - pathology Gestational Age Humans Matrix Metalloproteinase 9 - physiology Medical genetics Medical sciences Metabolic diseases Mice Mice, Transgenic Middle Aged Miscellaneous Nerve Growth Factor - biosynthesis Nerve Growth Factor - metabolism Nerve Growth Factor - physiology Neurology Organic mental disorders. Neuropsychology Original Other metabolic disorders Prosencephalon - enzymology Prosencephalon - metabolism Prosencephalon - pathology Protein Precursors - physiology Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry |
| Title | Nerve growth factor metabolic dysfunction in Down’s syndrome brains |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/24519975 https://www.proquest.com/docview/1500689331 https://www.proquest.com/docview/1505345210 https://pubmed.ncbi.nlm.nih.gov/PMC3927704 |
| Volume | 137 |
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