p75 neurotrophin receptor protects primary cultures of human neurons against extracellular amyloid beta peptide cytotoxicity.
The cytotoxicity of extracellular amyloid beta peptide (Abeta) has been clearly demonstrated in many cell types. In contrast, primary human neurons in culture are resistant to extracellular Abeta-mediated toxicity. Here, we investigate the involvement of p75 neurotrophin receptor (p75NTR) in Abeta-treated human neurons. We find that Abeta1-40 and Abeta1-42, but not the reverse control peptide, Abeta40-1, rapidly increase the levels of p75NTR in a specific and dose-dependent manner. In contrast to observations in cell lines, enhanced expression of p75NTR in human neurons via a herpes simplex virus amplicon vector does not increase the susceptibility of neurons to Abeta. Unexpectedly, inhibition of p75NTR expression with an antisense expression construct or incubation of the cells with an antibody to the extracellular domain of p75NTR sensitizes human neurons to extracellular nonfibrillar or fibrillar Abeta1-42 cytotoxicity. Unlike intracellular Abeta, extracellular Abeta toxicity is independent of p53 and Bax activity. However, Abeta toxicity is inhibited by caspase inhibitors and the glycogen synthase kinase 3beta inhibitor lithium. Neuroprotection against Abeta is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75NTR against extracellular Abeta toxicity in human neurons.
Zhang
Yan
Y
Department of Neurology and Center for Aging and Developmental Biology, University of Rochester, Rochester, New York 14642, USA.
Hong
Yanguo
Y
Bounhar
Younes
Y
Blacker
Megan
M
Roucou
Xavier
X
Tounekti
Omar
O
Vereker
Emily
E
Bowers
William J
WJ
Federoff
Howard J
HJ
Goodyer
Cynthia G
CG
LeBlanc
Andrea
A
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000096:biosynthesis / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
D016229:Amyloid beta-Peptides; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018021:Lithium Chloride; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C494918:AKT1 protein, human