Research in the last decade indicates that reduced cerebral glucose utilization is an early sign of AD that correlates with clinical progression of th disease. In vivo imaging studies indicate severe reduction of glucose metabolism in regions of the AD brain affected at early stages of the disease such as hippocampus, entorhinal formation and temporal cortex. Reduction in brain glucose metabolism is also observed in familial AD (FAD) patients and may occur years before disease onset in carriers of presenilin-1 (PS1) FAD mutations implicating PS1 in the regulation of brain metabolic activity. Glucose deprivation leads to neuronal death, a process associated with expression changes of genes involved in neuronal survival. In recent years a new mechanism of transcriptome regulation via the action of microRNAs (miRs) has emerged. MiRs are short, non-coding RNAs that suppress gene expression by post-transcriptional mechanisms including destabilization and inhibition of translation of mRNAs. By regulating gene expression, miRs regulate physiological processes including neuronal survival, synaptic plasticity and memory and emerging evidence supports a role for miRs in neurodegenerative disorders. We obtained evidence that the PS1/?-secretase system regulates the expression of miR-212 that targets the mRNA of PED/PEA-15 (PEA15), a protein known to promote cell survival under reduced glucose. We also observed that absence of PS1 sensitizes neurons to glucose deprivation and correlates with increased expression of neuronal miR-212 and decreased levels of both PEA15 mRNA and protein. Furthermore, we obtained evidence that PS/?-secretase regulate neuronal survival by controlling the expression of miR-212. Based on our data, we hypothesize that the increased expression of miR-212 and the resultant decrease in PEA15 contribute to the increased vulnerability displayed by PS1 null neurons under reduced glucose. Importantly, in this submission, we present new data that downregulation of neuronal PS1 with siRNA technology increases miR-212 and decreases PEA15 indicating PS1 controls a cascade that regulates production of cell survival factor PEA15. Here we examine the relationship between PS1, miR-212 and its target protein PEA15 and test their effects on neuronal survival under stress conditions. In addition, we ask how the ?-secretase function affects miR-212 and PEA15 and whether PS1/?-secretase modulate the glucose deprivation-induced survival signaling of PEA15. We also ask whether expression of miR-212 and its target PEA15 protein changes in brains of AD patients and in FAD mutant knockin animal models. Our data may indicate whether PS1 promotes neuronal survival by controlling the PS1/miR- 212/PEA15 cascade and whether antagonists of miR-212 rescue neurons from stress-induced death.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG008200-25
Application #
8741899
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Petanceska, Suzana
Project Start
1988-08-01
Project End
2018-04-30
Budget Start
2014-08-01
Budget End
2015-04-30
Support Year
25
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10029
Huang, Qian; Voloudakis, Georgios; Ren, Yimin et al. (2018) Presenilin1/?-secretase protects neurons from glucose deprivation-induced death by regulating miR-212 and PEA15. FASEB J 32:243-253
Warren, Noel A; Voloudakis, Georgios; Yoon, Yonejung et al. (2018) The product of the ?-secretase processing of ephrinB2 regulates VE-cadherin complexes and angiogenesis. Cell Mol Life Sci 75:2813-2826
Nikolakopoulou, Angeliki M; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2016) Presenilin 1 promotes trypsin-induced neuroprotection via the PAR2/ERK signaling pathway. Effects of presenilin 1 FAD mutations. Neurobiol Aging 42:41-9
Moreno, José L; Miranda-Azpiazu, Patricia; García-Bea, Aintzane et al. (2016) Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia. Sci Signal 9:ra5
Zhu, Li; Zhong, Minghao; Elder, Gregory A et al. (2015) Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer's disease pathogenesis. Proc Natl Acad Sci U S A 112:11965-70
Bruban, Julien; Voloudakis, Georgios; Huang, Qian et al. (2015) Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via ?-secretase-independent transcriptional mechanisms. FASEB J 29:3702-12
Barthet, Gael; Dunys, Julie; Shao, Zhiping et al. (2013) Presenilin mediates neuroprotective functions of ephrinB and brain-derived neurotrophic factor and regulates ligand-induced internalization and metabolism of EphB2 and TrkB receptors. Neurobiol Aging 34:499-510
Barthet, Gael; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2012) Cellular mechanisms of ýý-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166-75
Georgakopoulos, Anastasios; Xu, Jindong; Xu, Chijie et al. (2011) Presenilin1/gamma-secretase promotes the EphB2-induced phosphorylation of ephrinB2 by regulating phosphoprotein associated with glycosphingolipid-enriched microdomains/Csk binding protein. FASEB J 25:3594-604
Xu, Jindong; Xilouri, Maria; Bruban, Julien et al. (2011) Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. Neurobiol Aging 32:2326.e5-16

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