Journal of In Silico & In Vitro Pharmacology

Abstract

The two-hit hypothesis of Alzheimer suggests cell cycle entry is a major factor in driving neuronal death in Alzheimer’s disease (AD). We experimentally addressed this issue by driving c-myc expression specifically in neurons with an inducible cam-kinase promoter. We confirmed that c-myc was specifically inducible in large cortical/hippocampal neurons. We found expression of c-myc led to histone phosphorylation, DNA fragmentation (TUNEL), gliosis, and neuronal death. The effects were specific to brain areas of increased expression and did not involve the cerebellum. Consistent with neuronal specificity, behavior analysis showed the deficits were cognitive rather than motor function. These findings support cell cycle re-entry as a critical hit of the two-hit hypothesis of AD and point to the attractiveness of intervention to modify neuronal cell cycle re-entry as a therapeutic target.