Glutamate-induced excitotoxicity and oxidative stress are mechanisms implicated in the pathogenesis of Alzheimer's disease (AD). We found that ephrinB ligands (ephrinBLs) protect primary neuronal cultures from glutamate- and oxidative stress-induced toxicity and that the neuroprotective activities of ephrinBLs depend on EphB receptors (EphBRs) and presenilini (PS1), a protein involved in familial AD (FAD). We also observed that PS1 mediates the neuroprotective effects of brain-derived neurotrophic factor (BDNF). Interestingly, the neuroprotective activities of ephrinBLs and BDNF depend on both alleles of PS1 because absence of either one or both alleles results in the inhibition of trophic factor-induced neuroprotection. Furthermore, the neuroptotective activities of ephrinBLs and BDNF are significantly reduced in neurons either heterozygous or homozygous for FAD mutants of PS1. In contrast, the neuroprotective function of basic fibroblast growth factor (bFGF) is affected neither by WT nor by mutant PSl Our data suggest a novel mechanism of neurodegeneration in FAD where brain neurons expressing FAD mutants of PS1 may have reduced ability to respond to neuroprotective factors and therefore are more vulnerable to toxic insults then wild type neurons. This decreased neuroprotection may result in increased rates of neuronal loss and over many years, in severe depletion of neuronal populations. Here we propose tp investigate further the effects of PS1 and its FAD mutants oh the neuroprotective function of trophic factors in vitro using primary neuronal cultures and in vivo using PS1 knockout and FAD knock-in mouse models. We will use the same technology we employed for PS1 to explore the neuroprotective activities of presenilin 2 (PS2) and the amyloid precursor protein (APP). In addition, we will explore mechanisms involved in the neuroprotective function of PS1 including the role of MP/y-secretase receptor processing and endocytosis in the neuroprotecive activities of PS1, BDNF and ephrinBLs and the effects of PS1 and FAD mutants on ligand-induced receptor phosphorylation and downstream signaling.

Public Health Relevance

Excitotoxicity and oxidative stress are implicated in neurodegeneration and Alzheimer disease (AD). We found that PSl, a protein involved in familial AD, mediates the neuroprotective functions of brain factors like ephrinB and BDNF. These factors are unable to protect neurons in the absence of PS1. Interestingly, genetic changes that promote AD interfere with the neuroprotective function of PS1. Our findings have implications for the mechanism of neurodegeneration and mav provide novel targets for therapeutic intervention in AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG017926-13
Application #
8279299
Study Section
Special Emphasis Panel (NSS)
Program Officer
Refolo, Lorenzo
Project Start
2000-05-01
Project End
2015-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
13
Fiscal Year
2012
Total Cost
$334,591
Indirect Cost
$137,192
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
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
Bruban, Julien; Voloudakis, Georgios; Huang, Qian et al. (2015) Presenilin 1 is necessary for neuronal, but not glial, EGFR expression and neuroprotection via γ-secretase-independent transcriptional mechanisms. FASEB J 29:3702-12
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
Roussos, Panos; Mitchell, Amanda C; Voloudakis, Georgios et al. (2014) A role for noncoding variation in schizophrenia. Cell Rep 9:1417-29
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
Robakis, Nikolaos K (2014) Cell signaling abnormalities may drive neurodegeneration in familial Alzheimer disease. Neurochem Res 39:570-5
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/γ-secretase controls glutamate release, tyrosine phosphorylation, and surface expression of N-methyl-D-aspartate receptor (NMDAR) subunit GluN2B. J Biol Chem 288:30495-501
Barthet, Gael; Georgakopoulos, Anastasios; Robakis, Nikolaos K (2012) Cellular mechanisms of ýý-secretase substrate selection, processing and toxicity. Prog Neurobiol 98:166-75

Showing the most recent 10 out of 29 publications