Proteins with pathogenic polyglutamine expansion inhibit fast axonal transport

The mechanisms underlying neuronal degeneration in Alzheimer's disease (AD) are very controversial and none more so than whether apoptosis plays a role. Although neurons in AD face a wide assortment of apoptogenic stimuli, the temporal dichotomy between the acuteness of apoptosis vs. the chronicity of AD suggests that apoptosis should be extremely rare in AD. In this regard, survival factor(s) must be involved. In this study, we investigated Bcl-w, a pro-survival member of the Bcl-2 family. Although expressed at low levels in brains of control cases, Bcl-w is significantly up-regulated in AD as shown by both immunocytochemistry and immunoblot analysis. Astonishingly, increased Bcl-w was found to be associated with neurofibrillary pathologies in AD, which was further demonstrated by an EM study. Since neuronal death in AD is thought to be triggered by increased production of amyloid-β (Aβ), it was interesting to find that exposure of human M17 neuroblastoma cells to Aβ1–42 (1 n m −10 μ m ) dramatically up-regulates Bcl-w protein levels. Such increases may be a protective response that attenuates apoptotic processes. Consistent with this, transfected M17 cells overexpressing Bcl-w were protected from both STS-induced and Aβ-induced apoptosis compared to vector-transfected controls. Notably, both tau phosphorylation and p38 is inhibited in Bcl-w transfected cells which may contribute to the neuroprotective role of Bcl-w. Taken together, these set of in vitro and in vivo results suggest that Bcl-w plays an important protective role in neurons in the AD brain.