Excitotoxicity, a form of neuronal damage due to excessive activation of glutamate receptors and oxidative stress are mechanisms of neuronal injury implicated in the pathogenesis of Alzheimer's disease (AD). We found that the ephrinB family of ligand proteins protects primary neuronal cultures from both glutamate- and oxidative stress- induced death. The neuroprotective activities of ephrinB ligands (ephrinBLs) are mediated by their receptors (EphB receptors, EphBRs) and depend on PS1, a protein involved in familial AD (FAD). Interestingly, the neuroprotective effect of ephrinB depends on both PS1 alleles because absence of one allele (haploinsufficiency) results in severe reduction of the ephrinB neuroprotection. Furthermore, we obtained preliminary data that FAD mutants of PS1 interfere with the ephrinB-dependent neuroprotection and that -secretase activity may be involved in the neuroprotective functions of the ephrinBL/EphBR system. Here we propose to further investigate the effects of PS1 FAD mutants and -secretase on the neuroprotective function of ephrinBLs and to elucidate molecular mechanisms by which PS1 mediates this function. We will explore whether PS1 regulates the binding of ephrinBLs to EphBRs and the ephrinBL-induced phosphorylation of both EphB and NMDA receptors. To this end we will use cortical primary neuronal cultures from our PS1 knockout and FAD mutant knock-in transgenic mouse colonies as well as EphBR knock-out colonies available in our laboratory. We will also use our mouse models to examine the neuroprotective function of the ephriBL/EphBR system in vivo and to ask whether PS1 FAD mutations affect this function. Finally, we will ask whether PS2, a homologue of PS1 also involved in FAD, may also be involved in the ephrinB neuroprotection.

Public Health Relevance

Excitotoxicity and oxidative stress are neurotoxic mechanisms implicated in the neurodegeneration of Alzheimer's disease (AD). We found that a protein called ephrinB, has neuroprotective functions and rescues neurons from excitotoxic and oxidative death;these neuroprotective effects of ephrinB depend on PS1, a protein involved in AD. Our findings have implications for the mechanisms by which genetic mutations cause neurodegeneration and may provide novel targets for therapeutic intervention in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS047229-08
Application #
8271402
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Corriveau, Roderick A
Project Start
2004-01-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
8
Fiscal Year
2012
Total Cost
$363,366
Indirect Cost
$148,991
Name
Icahn School of Medicine at Mount Sinai
Department
Psychiatry
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Robakis, Nikolaos K; Georgakopoulos, Anastasios (2014) Allelic interference: a mechanism for trans-dominant transmission of loss of function in the neurodegeneration of familial Alzheimer's disease. Neurodegener Dis 13:126-30
Roussos, Panos; Mitchell, Amanda C; Voloudakis, Georgios et al. (2014) A role for noncoding variation in schizophrenia. Cell Rep 9:1417-29
Zhu, Li; Zhong, Minghao; Zhao, Jiaying et al. (2013) Reduction of synaptojanin 1 accelerates A* clearance and attenuates cognitive deterioration in an Alzheimer mouse model. J Biol Chem 288:32050-63
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
Xuan, Zhao; Barthet, Gael; Shioi, Junichi et al. (2013) Presenilin-1/ýý-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B. J Biol Chem 288:30495-501
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
Barthet, Gael; Shioi, Junichi; Shao, Zhiping et al. (2011) Inhibitors of ýý-secretase stabilize the complex and differentially affect processing of amyloid precursor protein and other substrates. FASEB J 25:2937-46
Kouchi, Zen; Barthet, Gael; Serban, Geo et al. (2009) p120 catenin recruits cadherins to gamma-secretase and inhibits production of Abeta peptide. J Biol Chem 284:1954-61
Baki, Lia; Neve, Rachael L; Shao, Zhiping et al. (2008) Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling. J Neurosci 28:483-90
Fassa, Angeliki; Parisiadou, Loukia; Robakis, Nikolaos K et al. (2007) Novel processing of Notch 1 within its intracellular domain by a cysteine protease. Neurodegener Dis 4:148-55

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