Brain-derived neurotrophic factor activation of TrkB protects neurons from HIV-1/gp120-induced cell death.
Patients with the human immunodeficiency virus type 1 (HIV-1) develop in the late phase of infection a complex of neurological signs termed Acquired Immune Deficiency Syndrome-Related Dementia (ADC). These patients exhibit cortical and subcortical atrophy. Considerable experimental data indicate that the HIV-1 envelope glycoprotein gp120 may be one of the agents causing neuronal cell death. Gp120 causes neuronal cell death both in vitro and in vivo by activating a caspase-dependent apoptotic pathway, and in particular caspase-3. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to prevent gp120-mediated apoptosis of cerebellar granule cells by inhibiting caspase-3 activation. However, the signal transduction pathway that contributes to the neuroprotective effects of BDNF has not been determined. BDNF binds with high affinity to the tyrosine kinase receptor TrkB and activates different intracellular signaling cascade including the extracellular signal-related kinases (ERK) and the phosphatidylinositol 3-kinase (PI3-K). Pharmacological inhibition of TrkB or ERK1/2, but not PI3-K, greatly reduced the ability of BDNF to block gp120-mediated apoptosis of cerebellar granule cells. These findings suggest that TrkB-mediated activation of ERK1/2 is the main signaling pathway that contributes to neuroprotection against gp120.
Mocchetti
Italo
I
Department of Neuroscience, Georgetown University Medical Center, Washington DC 20057, USA. moccheti@georgetown.edu
Bachis
Alessia
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D005786:Gene Expression Regulation / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000633:toxicity*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D020813:Receptor, trkB / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D020813:Receptor, trkB; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases