: This application is a competing renewal of an R29 grant, """"""""ApoE and its receptors in normal and Alzheimer's brain."""""""" ApoE (apolipoprotein E) remains the best-defined genetic risk factor for late onset Alzheimer disease (AD). ApoE is involved in cholesterol transport and, in AD, is associated with Abeta deposits. A number of in vitro and invivo studies have shown that apoE binds to the Abeta peptide, and affects both its clearance and its aggregation. ApoE is cleared by a family of cell surface receptors, members of the low-density lipoprotein (LDL) receptor family. We found expression of these receptors in subsets of cells in the CNS, focusing our attention primarily on the LDL receptor related protein, LRP. Polymorphisms in LRP may also affect the risk of AD, and in vitro, LRP can promote endocytosis of Abeta complexed to LRP ligands. In this proposal, we will continue to focus on endocytosis of apoE and Abeta via this family of receptors, but we will also expand our studies to look at other members of the LDL receptor family, including the VLDL receptor and apoE receptor 2. In addition, we will address newly identified functions of these receptors as signal transduction molecules. For example, in response to ligand binding, these receptors have been shown to affect calcium influx, protein phosphorylation, and glial activation. We propose that the deposition of apoE and related molecules on Abeta deposits in the AD brain affects the function of surrounding neurons and glia via these receptors. These ligand-receptor interactions could help explain the connection between amyloid deposits and formation of phospho-tau positive neurites in the AD brain.
Aim 1. We hypothesize that clearance of apoE and lipoprotein-associated molecules interact with the VLDL receptor and apoEr2. A) We will test whether apoE isoforms, apolipoprotein J (apoJ) and lipoprotein lipase (LPL) are cleared by the VLDL receptor or apoEr2. B) We will test whether these receptors, present on microglia and neurons, act as clearance mechanisms for Abeta. C) We will measure the presence of apoJ and LPL in the AD brain, testing whether either affects the processes of amyloid deposition and dystrophic neurite formation. D) We will determine if polymorphisms in these genes may also affect the risk of AD.
Aim 2. We hypothesize that the signaling functions of apoEr2 and the VLDL receptor cause neuronal dysfunction seen in AD. A) We will test whether these receptors interact with several hypothesized signal transduction molecules (including disabled) invivo. B) We will test whether these molecules are important for calcium influx and neurite outgrowth in neurons and activation of glia. C) We will test whether these molecules are involved in the phosphorylation of tau observed in neurofibrillary tangles of AD brains.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014473-09
Application #
6837605
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Petanceska, Suzana
Project Start
1996-08-05
Project End
2006-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
9
Fiscal Year
2005
Total Cost
$301,088
Indirect Cost
Name
Georgetown University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
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Minami, S Sakura; Clifford, Thomas G; Hoe, Hyang-Sook et al. (2012) Fyn knock-down increases A?, decreases phospho-tau, and worsens spatial learning in 3×Tg-AD mice. Neurobiol Aging 33:825.e15-24
Minami, S Sakura; Hoe, Hyang-Sook; Rebeck, G William (2011) Fyn kinase regulates the association between amyloid precursor protein and Dab1 by promoting their localization to detergent-resistant membranes. J Neurochem 118:879-90
Burns, Mark P; Rebeck, G William (2010) Intracellular cholesterol homeostasis and amyloid precursor protein processing. Biochim Biophys Acta 1801:853-9
Cartagena, Casandra M; Burns, Mark P; Rebeck, G William (2010) 24S-hydroxycholesterol effects on lipid metabolism genes are modeled in traumatic brain injury. Brain Res 1319:1-12
Minami, S Sakura; Sung, You Me; Dumanis, Sonya B et al. (2010) The cytoplasmic adaptor protein X11alpha and extracellular matrix protein Reelin regulate ApoE receptor 2 trafficking and cell movement. FASEB J 24:58-69
Pocivavsek, Ana; Mikhailenko, Irina; Strickland, Dudley K et al. (2009) Microglial low-density lipoprotein receptor-related protein 1 modulates c-Jun N-terminal kinase activation. J Neuroimmunol 214:25-32
Hoe, Hyang-Sook; Lee, Kea Joo; Carney, Rosalind S E et al. (2009) Interaction of reelin with amyloid precursor protein promotes neurite outgrowth. J Neurosci 29:7459-73
Pocivavsek, Ana; Rebeck, G William (2009) Inhibition of c-Jun N-terminal kinase increases apoE expression in vitro and in vivo. Biochem Biophys Res Commun 387:516-20
Pocivavsek, Ana; Burns, Mark P; Rebeck, G William (2009) Low-density lipoprotein receptors regulate microglial inflammation through c-Jun N-terminal kinase. Glia 57:444-53

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