APOE is the strongest genetic risk factor for Alzheimer's disease and many of its actions in the brain are mediated by specific apoE receptors. Over the past several years, we have defined various signaling roles for apoE and apoE receptors in the brain, and examined how they affect neuronal physiology and animal behavior. In this proposal, we are focusing on one of the most interesting synaptic apoE receptors, ApoER2, and its mechanism of function as a synaptic signaling molecule. Furthermore, we are addressing how the three human apoE isoforms differ in their interactions with ApoER2, using APOE targeted replacement mice. This project is a collaboration between two investigators at two sites, to make use of common interests in ApoER2 signaling and diverse experimental techniques. By conducting both in vitro and in vivo experiments, we will be able to test the in vivo relevance to in vitro findings and design in vitro experiments to define mechanisms for in vivo findings. There are four specific aims;the first three examine the neuronal signaling functions of apoE isoforms via ApoER2;the last one examines how those functions may contribute to pathogenic processes of neurodegeneration. 1. We will determine the in vivo effects of the three human apoE isoforms on neuronal structure and synaptic function;2. We will define mechanisms of ApoER2 effects on neuronal signaling in vitro;3. We will define how ApoER2 affects neuronal signaling in vivo;and 4. We will translate these basic findings into two approaches to protecting against synaptic loss in models with Alzheimer's disease pathological changes. These connected and complementary aims will allow us to define important roles of apoE isoforms in normal neuronal function, which may contribute to the associated risk of AD. These experiments also address new functions of apoE receptors in neuronal signaling, defining mechanisms by which these receptors alter synaptic function. They also explore the role of receptor clustering in normal receptor signaling mechanisms. Finally, they will test two important hypotheses about how APOE genotype alters the risk of Alzheimer's disease, translating preliminary findings about JNK activation and ApoER2 receptor clustering into approaches to prevent the synaptic dysfunction associated with neurodegeneration.
Alzheimer's disease affects over 5 million people in the USA already, and the numbers will triple in 40 years giving the increasing numbers of aged citizens. APOE is the strongest genetic risk factor for Alzheimer's disease, influencing over half of all cases, but we do not know how it influences the disease. This proposed research will address the actions of apoE in the brain, and identify ways that it could be affecting Alzheimer's disease.
|Lussier, April L; Weeber, Edwin J; Rebeck, G William (2016) Reelin Proteolysis Affects Signaling Related to Normal Synapse Function and Neurodegeneration. Front Cell Neurosci 10:75|
|Hethorn, Whitney R; Ciarlone, Stephanie L; Filonova, Irina et al. (2015) Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome. Eur J Neurosci 41:1372-80|
|Green, Adam E; Gray, Jeremy R; Deyoung, Colin G et al. (2014) A combined effect of two Alzheimer's risk genes on medial temporal activity during executive attention in young adults. Neuropsychologia 56:1-8|
|Zhao, Wenjuan; Dumanis, Sonya B; Tamboli, Irfan Y et al. (2014) Human APOE genotype affects intraneuronal A?1-42 accumulation in a lentiviral gene transfer model. Hum Mol Genet 23:1365-75|
|Divekar, Shailaja D; Burrell, Teal C; Lee, Jennifer E et al. (2014) Ligand-induced homotypic and heterotypic clustering of apolipoprotein E receptor 2. J Biol Chem 289:15894-903|
|Rodriguez, Gustavo A; Tai, Leon M; LaDu, Mary Jo et al. (2014) Human APOE4 increases microglia reactivity at A? plaques in a mouse model of A? deposition. J Neuroinflammation 11:111|
|Burrell, Teal C; Divekar, Shailaja D; Weeber, Edwin J et al. (2014) Fyn tyrosine kinase increases Apolipoprotein E Receptor 2 levels and phosphorylation. PLoS One 9:e110845|
|Tamboli, Irfan Y; Heo, Dongeun; Rebeck, G William (2014) Extracellular proteolysis of apolipoprotein E (apoE) by secreted serine neuronal protease. PLoS One 9:e93120|
|Trotter, J H; Lussier, A L; Psilos, K E et al. (2014) Extracellular proteolysis of reelin by tissue plasminogen activator following synaptic potentiation. Neuroscience 274:299-307|
|Stevens, Benson W; DiBattista, Amanda M; William Rebeck, G et al. (2014) A gene-brain-cognition pathway for the effect of an Alzheimer?s risk gene on working memory in young adults. Neuropsychologia 61:143-9|
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