Modulation of neuronal thread protein expression with neuritic sprouting: relevance to Alzheimer's disease

Widespread proliferation of dystrophic neurites in the cerebral cortex represents an important neuroanatomical correlate of dementia in Alzheimer's disease (AD). Increased CNS expression of the 21-kDa neuronal thread protein (NTP) species is also correlated with dementia in AD. Pilot in vitro experiments provided evidence that high-level NTP expression might be linked to neuritic growth. The present study examines retinoic acid (RA) modulation of NTP expression during neurite outgrowth and neuronal differentiation in SH-Sy5y neuroblastoma and PNET2 CNS-derived cells. In both cell lines, RA-induced neuronal differentiation resulted in increased synthesis, expression, and phosphorylation of several NTP species, with high steady-state levels and stepwise hyper-phosphorylation of 21-kDa NTP molecules. With neurite outgrowth, NTP molecules were translocated from the perikarya to long, slender, unbranched cell processes (axons) and growth cones. RA-mediated changes in NTP expression were independent of DNA synthesis. The findings suggest that high-level expression of 21-kDa, and closely related phosphorylated NTP molecules correlates with neuritic growth. Therefore, over-expression of 21-kDa NTP molecules in AD probably reflects the widespread cortical neuritic sprouting associated with dementia. In view of the rapid phosphorylation and cell process translocation of NTP that occurs during neurite outgrowth in vitro, the accumulation of NTP in AD cortical neuronal perikarya suggests a further problem related to post-translational processing and transport of NTP molecules in AD neurodegeneration.