Prion protein prevents Bax-mediated cell death in the absence of other Bcl-2 family members in Saccharomyces cerevisiae.

Although there is no consensus regarding the normal function of the prion protein, increasing evidence points towards a role in cellular protection against cell death. We have previously shown that prion protein is a potent inhibitor of Bax-induced apoptosis in human primary neurons and in the breast carcinoma MCF-7 cells. Here, we used the yeast Saccharomyces cerevisiae to investigate if the neuroprotective function of prion protein requires other members of the Bcl-2 family given that S. cerevisiae lacks Bcl-2 genes but undergoes a mitochondrial-dependent apoptotic cell death upon exogenous expression of Bax protein. We show that Bax induces cell death and growth inhibition in S. cerevisiae. Prion protein prevents Bax-mediated cell death. Prion protein overcomes Bax-mediated growth arrest in S phase but cannot overcome population growth inhibition because the cells then accumulate in G(2)/M phase. We conclude that prion protein does not require other Bcl-2 family proteins to protect against Bax-mediated cell death.

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.