RT Journal Article
SR Electronic
T1 Neurons in Vulnerable Regions of the Alzheimer’s Disease Brain Display Reduced ATM Signaling
JF eneuro
JO eneuro
FD Society for Neuroscience
SP ENEURO.0124-15.2016
DO 10.1523/ENEURO.0124-15.2016
VO 3
IS 1
A1 Xuting Shen
A1 Jianmin Chen
A1 Jiali Li
A1 Julia Kofler
A1 Karl Herrup
YR 2016
UL http://www.eneuro.org/content/3/1/ENEURO.0124-15.2016.abstract
AB Ataxia telangiectasia (A-T) is a multisystemic disease caused by mutations in the ATM (A-T mutated) gene. It strikes before 5 years of age and leads to dysfunctions in many tissues, including the CNS, where it leads to neurodegeneration, primarily in cerebellum. Alzheimer’s disease (AD), by contrast, is a largely sporadic neurodegenerative disorder that rarely strikes before the 7th decade of life with primary neuronal losses in hippocampus, frontal cortex, and certain subcortical nuclei. Despite these differences, we present data supporting the hypothesis that a failure of ATM signaling is involved in the neuronal death in individuals with AD. In both, partially ATM-deficient mice and AD mouse models, neurons show evidence for a loss of ATM. In human AD, three independent indices of reduced ATM function—nuclear translocation of histone deacetylase 4, trimethylation of histone H3, and the presence of cell cycle activity—appear coordinately in neurons in regions where degeneration is prevalent. These same neurons also show reduced ATM protein levels. And though they represent only a fraction of the total neurons in each affected region, their numbers significantly correlate with disease stage. This previously unknown role for the ATM kinase in AD pathogenesis suggests that the failure of ATM function may be an important contributor to the death of neurons in AD individuals.