Regional hippocampal differences in AKT survival signaling across the lifespan: implications for CA1 vulnerability with aging.
Distinct neuronal populations differ by the degree of damage caused from cellular stress. Hippocampal neurons of area CA1 are especially vulnerable to several stressors that increase as age advances. We show here that survival signaling, as measured by activated protein kinase B (AKT), was significantly reduced in the nuclear CA1 region across the lifespan compared with CA3. In agreement with these findings, the pro-apoptotic protein and AKT nuclear substrate, forkhead box O3a transcription factor (FOXO3a), were significantly higher in CA1. Further, regional differences in PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1), a recently discovered inhibitor of AKT, inversely correlated with nuclear phosphorylated AKT at Ser473. Altogether, our data suggest that regional differences in nuclear levels of activated AKT may contribute to regional differences in hippocampal vulnerability and implicate PHLPP1 as a potential target for therapeutic intervention to improve hippocampal health.
Jackson
T C
TC
Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32610-0244, USA.
Rani
A
A
Kumar
A
A
Foster
T C
TC
D000375:Aging / Q000502:physiology*; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology / Q000502:physiology; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D009687:Nuclear Proteins; D017526:Receptor, IGF Type 1; D051057:Proto-Oncogene Proteins c-akt