Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor
Activation of the p75 neurotrophin receptor (p75NTR), by the proneurotrophin brain-derived neurotrophic factor (proBDNF), triggers loss of synapses and promotes neuronal death. These pathological features are also caused by the human immunodeficiency virus-1 (HIV) envelope protein gp120, which incre...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-08-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fncel.2019.00398/full |
| _version_ | 1818989407241240576 |
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| author | Andrew Speidell Gino Paolo Asuni Valeria Avdoshina Serena Scognamiglio Patrick Forcelli Italo Mocchetti |
| author_facet | Andrew Speidell Gino Paolo Asuni Valeria Avdoshina Serena Scognamiglio Patrick Forcelli Italo Mocchetti |
| author_sort | Andrew Speidell |
| collection | DOAJ |
| description | Activation of the p75 neurotrophin receptor (p75NTR), by the proneurotrophin brain-derived neurotrophic factor (proBDNF), triggers loss of synapses and promotes neuronal death. These pathological features are also caused by the human immunodeficiency virus-1 (HIV) envelope protein gp120, which increases the levels of proBDNF. To establish whether p75NTR plays a role in gp120-mediated neurite pruning, we exposed primary cultures of cortical neurons from p75NTR–/– mice to gp120. We found that the lack of p75NTR expression significantly reduced gp120-mediated neuronal cell death. To determine whether knocking down p75NTR is neuroprotective in vivo, we intercrossed gp120 transgenic (tg) mice with p75NTR heterozygous mice to obtain gp120tg mice lacking one or two p75NTR alleles. The removal of p75NTR alleles inhibited gp120-mediated decrease of excitatory synapses in the hippocampus, as measured by the levels of PSD95 and subunits of the N-methyl-D-Aspartate receptor in synaptosomes. Moreover, the deletion of only one copy of the p75NTR gene was sufficient to restore the cognitive impairment observed in gp120tg mice. Our data suggest that activation of p75NTR is one of the mechanisms crucial for the neurotoxic effect of gp120. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by HIV. |
| first_indexed | 2024-12-20T19:37:59Z |
| format | Article |
| id | doaj.art-087b2e3a5a0647c6aefb13841ba2f856 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-20T19:37:59Z |
| publishDate | 2019-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-087b2e3a5a0647c6aefb13841ba2f8562022-12-21T19:28:36ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022019-08-011310.3389/fncel.2019.00398462023Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin ReceptorAndrew Speidell0Gino Paolo Asuni1Valeria Avdoshina2Serena Scognamiglio3Patrick Forcelli4Italo Mocchetti5Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United StatesLaboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United StatesLaboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United StatesLaboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United StatesDepartment of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC, United StatesLaboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, United StatesActivation of the p75 neurotrophin receptor (p75NTR), by the proneurotrophin brain-derived neurotrophic factor (proBDNF), triggers loss of synapses and promotes neuronal death. These pathological features are also caused by the human immunodeficiency virus-1 (HIV) envelope protein gp120, which increases the levels of proBDNF. To establish whether p75NTR plays a role in gp120-mediated neurite pruning, we exposed primary cultures of cortical neurons from p75NTR–/– mice to gp120. We found that the lack of p75NTR expression significantly reduced gp120-mediated neuronal cell death. To determine whether knocking down p75NTR is neuroprotective in vivo, we intercrossed gp120 transgenic (tg) mice with p75NTR heterozygous mice to obtain gp120tg mice lacking one or two p75NTR alleles. The removal of p75NTR alleles inhibited gp120-mediated decrease of excitatory synapses in the hippocampus, as measured by the levels of PSD95 and subunits of the N-methyl-D-Aspartate receptor in synaptosomes. Moreover, the deletion of only one copy of the p75NTR gene was sufficient to restore the cognitive impairment observed in gp120tg mice. Our data suggest that activation of p75NTR is one of the mechanisms crucial for the neurotoxic effect of gp120. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by HIV.https://www.frontiersin.org/article/10.3389/fncel.2019.00398/fullHIVMorris water mazeNMDA receptorsp75NTRpassive avoidanceproBDNF |
| spellingShingle | Andrew Speidell Gino Paolo Asuni Valeria Avdoshina Serena Scognamiglio Patrick Forcelli Italo Mocchetti Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor Frontiers in Cellular Neuroscience HIV Morris water maze NMDA receptors p75NTR passive avoidance proBDNF |
| title | Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor |
| title_full | Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor |
| title_fullStr | Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor |
| title_full_unstemmed | Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor |
| title_short | Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor |
| title_sort | reversal of cognitive impairment in gp120 transgenic mice by the removal of the p75 neurotrophin receptor |
| topic | HIV Morris water maze NMDA receptors p75NTR passive avoidance proBDNF |
| url | https://www.frontiersin.org/article/10.3389/fncel.2019.00398/full |
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