Testing The Two-hit Hypothesis Of Alzheimer?s Disease: Cell Cycle Re-entry | 12482
Journal of Alzheimers Disease & Parkinsonism
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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
George Perry is Dean of the College of Sciences and Professor of Biology at the University of Texas at San Antonio, and Adjunct Professor of
Pathology and Neurosciences at Case Western Reserve University. Perry is recognized in the field of Alzheimer?s disease research particularly
for his work on oxidative metabolism. He is distinguished as one of the top Alzheimer?s disease researchers with over 1000 publications, and one
of the top 100 most-cited scientists in neuroscience and behavior. Perry is editor-in-chief for the Journal of Alzheimer's Disease, a Fellow of the
American Association for the Advancement of Sciences, the Microscopy Society of America, the Royal Society of Chemistry, and past president
of the American Association of Neuropathologists, as well as a member of the Dana Alliance for Brain Initiatives and a Fulbright Senior Specialist.
Perry's research is primarily focused on how Alzheimer disease develops and the physiological consequences of the disease at a cellular level.
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