title: The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice.
abstract: Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR). Here, we have used gp120 transgenic (gp120tg) mice to investigate whether p75NTR has a role in gp120-mediated neurotoxicity. Old (∼10 months) gp120tg mice exhibited an increase in proneurotrophin brain-derived neurotrophic factor levels in the hippocampus as well as a decrease in the number of dendritic spines when compared to age-matched wild type. These effects were not observed in 3- or 6-month-old mice. To test if the reduction in spine density and morphology is caused by the activation of p75NTR, we crossed gp120tg mice with p75NTR null mice. We found that deletion of only 1 copy of the p75NTR gene in gp120tg mice is sufficient to normalize the number of hippocampal spines, strongly suggesting that the neurotoxic effect of gp120 is mediated by p75NTR. These data indicate that p75NTR antagonists could provide an adjunct therapy against synaptic simplification caused by human immunodeficiency virus 1.
authors: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors: Alessia
authors: A
authors: Bachis
authors: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA; Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA.
authors: Erin
authors: E
authors: Wenzel
authors: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
authors: Allyssia
authors: A
authors: Boelk
authors: Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
authors: Jodi
authors: J
authors: Becker
authors: Laboratory of Preclinical Neurobiology, Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA. Electronic address: moccheti@georgetown.edu.
authors: Italo
authors: I
authors: Mocchetti
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D049229:Dendritic Spines / Q000473:pathology* / Q000821:virology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D015658:HIV Infections / Q000150:complications / Q000821:virology; D015497:HIV-1; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D019965:Neurocognitive Disorders / Q000209:etiology / Q000473:pathology / Q000628:therapy; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000473:pathology* / Q000821:virology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D020800:Receptor, Nerve Growth Factor
keywords: Aging; HIV; Hippocampus; TrkB; p75NTR; proBDNF