p75 Neurotrophin Receptor Protects Primary Cultures of Human Neurons against Extracellular Amyloid β Peptide Cytotoxicity

The cytotoxicity of extracellular amyloid β peptide (Aβ) has been clearly demonstrated in many cell types. In contrast, primary human neurons in culture are resistant to extracellular Aβ-mediated toxicity. Here, we investigate the involvement of p75 neurotrophin receptor (p75NTR) in Aβ-treated human neurons. We find that Aβ1-40 and Aβ1-42, but not the reverse control peptide, Aβ40-1, 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 Aβ. 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 Aβ1-42 cytotoxicity. Unlike intracellular Aβ, extracellular Aβ toxicity is independent of p53 and Bax activity. However, Aβ toxicity is inhibited by caspase inhibitors and the glycogen synthase kinase 3β inhibitor lithium. Neuroprotection against Aβ is phosphatidylinositide 3-kinase dependent but Akt independent. These results are consistent with a neuroprotective role for p75NTR against extracellular Aβ toxicity in human neurons.