There is a functional connection between Apolipoprotein E (ApoE) and Alzheimer's disease. The underlying biochemical mechanism by which ApoE predisposes its carriers to this disease is not known and is under debate. One model suggests that members of a family of ApoE receptors that are abundantly expressed on the surface of neurons, specifically the ApoE2 and VLDL receptors, may be involved in this pathological process. Two of these ApoE receptors, the VLDL receptor and the ApoER2, are also receptors for Reelin, a signaling protein that regulates neuronal migration during brain development. Adult expression of Reelin by GABA-ergic interneurons coupled to a high expression of ApoE2 and VLDL receptors in the hippocampus strongly suggests a role for these systems in adult CNS. The basis for this proposal is the hypothesis that there is a function of the Reelin/ApoE2/VLDL receptor system as a modulator of neurotransmission in the adult CNS. To better understand the role of this receptor system in mammalian hippocampal function, we will undertake four specific aims: ? Aim 1: Determine if mice deficient for ApoE2 and VLDL receptors exhibit deficits in learning and memory and hippocampal synoptic function. ? Aim 2: Determine the effect of Reelin application and Reelin signaling disruption on adult hippocampal synaptic transmission and plasticity. ? Aim 3: Test the hypothesis that Reelin acts through Src tyrosine kinase to phosphorylate NMDA receptors in an ApoER2/VLDL receptor-dependent manner. ? Aim 4: Determine the structure/function relationship for ApoER2 cytoplasmic domains. ? These studies will provide a basic understanding of the role for the lipoprotein receptors ApoE2 and VLDL in mammalian learning and memory mechanisms and hippocampal synaptic transmission and plasticity. Moreover, these studies will provide the first insight into the mechanisms of Reelin signaling through these receptors to modulate hippocampal function. Overall, this work will help shed light on the potential role of these ApoE receptors in neurodegenerative disorders, such as Alzheimer's disease. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG022574-01A1
Application #
6781277
Study Section
Neurobiology of Learning and Memory Study Section (LAM)
Program Officer
Wagster, Molly V
Project Start
2004-06-01
Project End
2009-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
1
Fiscal Year
2004
Total Cost
$288,788
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Banko, Jessica L; Trotter, Justin; Weeber, Edwin J (2011) Insights into synaptic function from mouse models of human cognitive disorders. Future Neurol 6:113-125
Tanner, Daniel C; Qiu, Shenfeng; Bolognani, Federico et al. (2008) Alterations in mossy fiber physiology and GAP-43 expression and function in transgenic mice overexpressing HuD. Hippocampus 18:814-23
Bolognani, Federico; Qiu, Shenfeng; Tanner, Daniel C et al. (2007) Associative and spatial learning and memory deficits in transgenic mice overexpressing the RNA-binding protein HuD. Neurobiol Learn Mem 87:635-43
Gelinas, Jennifer N; Banko, Jessica L; Hou, Lingfei et al. (2007) ERK and mTOR signaling couple beta-adrenergic receptors to translation initiation machinery to gate induction of protein synthesis-dependent long-term potentiation. J Biol Chem 282:27527-35
Qiu, Shenfeng; Weeber, Edwin J (2007) Reelin signaling facilitates maturation of CA1 glutamatergic synapses. J Neurophysiol 97:2312-21
Qiu, Shenfeng; Zhao, Lisa F; Korwek, Kimberly M et al. (2006) Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J Neurosci 26:12943-55