Human immunodeficiency virus type 1 glycoprotein gp120 reduces the levels of brain-derived neurotrophic factor in vivo: potential implication for neuronal cell death.
Neuronal loss has been observed in post mortem brains of patients with human immunodeficiency virus type 1 (HIV-1). Experimental evidence has implicated HIV-1-derived envelope glycoprotein 120 (gp120) in the neuronal cell death observed in these patients. However, the intrinsic mechanisms by which gp120 causes neurotoxicity are still unknown. We have recently shown that the neurotoxic effect of gp120 in vitro is reduced by brain-derived neurotrophic factor (BDNF). We therefore tested the hypothesis that low levels of BDNF render neurons more sensitive to gp120. Gp120 was injected acutely into the striatum of BDNF heterozygous mice and wild-type littermates. BDNF heterozygous mice exhibited more apoptotic neurons in the striatum than wild-type mice, suggesting that BDNF is neuroprotective also in vivo. Because several neurodegenerative disorders are characterized by lack of trophic support, we tested the hypothesis that gp120 may cause apoptosis by reducing BDNF expression. Gp120 was injected acutely in the rat striatum and BDNF levels determined by a two-site immunoassay at various times after the injection. Gp120 elicited a dramatic decrease in BDNF protein levels by 24 h. Reduced BDNF levels were still present at 4 days. Cellular localization of BDNF immunoreactivity revealed that gp120 decreases BDNF immunoreactivity mainly in neuronal processes. This effect of gp120 precedes the peak of caspase-3 activation and neuronal cell death. We propose that one of the mechanisms whereby gp120 causes neurotoxicity is a reduction of the neurotrophic factor environment crucial for cell survival.
Nosheny
Rachel L
RL
Department of Neuroscience, Georgetown University, Washington, DC, USA.
Bachis
Alessia
A
Acquas
Elio
E
Mocchetti
Italo
I
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects*; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D007839:Functional Laterality / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D007211:Indoles / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D007211:Indoles; D014409:Tumor Necrosis Factor-alpha; C007293:DAPI; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases