Inheritance of the apolipoprotein (apo) E4 allele is the major identified genetic risk factor for sporadic Alzheimer's disease (AD). We suggested in 1992 that apoE, especially its apoE4 isoform, can promote the conformational change of amyloid beta (Abeta) from soluble Abeta to toxic aggregates and amyloid plaques and coined the term """"""""pathological chaperone"""""""" to describe this role. Many subsequent studies have been consistent with this hypothesis. In this proposal, based on our preliminary data, we plan to develop a novel, non-toxic therapeutic strategy for amyloid clearance in Alzheimer's disease, by blocking the apoE/Aa interaction. Based on the known binding site of apoE on Aa (Aa residues 12-28), we synthesized an end-protected, D-amino acid peptide Abeta12-28P, where the valine at residue 18 is substituted by proline. This modification renders the peptide non-toxic and non-fibrillogenic, without affecting binding to apoE. Abeta12-28P is blood-brain barrier permeable (clearance=65q20ul serum/g) and its serum half-life is 62q18 min. Our data shows this peptide reduces the Abeta/apoE toxicity and fibril formation in vitro. Transgenic APP/PS1 AD mice treated for one month with Abeta12-28P have a 63% reduced amyloid burden in the cortex (p=0.0048) and 62% in the hippocampus (p=0.0047) compared to controls. No toxicity was observed in the animals and no humoral response to Abeta was detected under our experimental conditions (so the treatment effect could not be due to antibody clearance of Abeta). Our preliminary data also indicates this treatment can reduce or remove existing amyloid lesions as documented by in vivo 2-photon imaging.
Our Specific Aims are: 1) To evaluate the effect of blocking the apoE/Abeta interaction on amyloid burden (by in vivo imaging and histology), neuronal pathology and behavior in Tg animal models of Alzheimer's disease. 2) To identify the Aa binding site on apo E, so that further inhibitors of the apoE/Aa interaction can be designed based on the apoE sequence where Abeta binds and to develop peptidomimetics based on both the Aa and apoE sequences. 3) To determine the effects of blocking the Abeta/apoE interaction on other apoE functions as assessed by hippocampal neuronal spine integrity and receptor binding. These studies will test our central hypothesis that blocking the Aa/apoE interaction can serve as a novel, non-toxic therapeutic target for Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG015408-06A1
Application #
6988313
Study Section
Special Emphasis Panel (ZRG1-CDIN (01))
Program Officer
Snyder, Stephen D
Project Start
1998-08-01
Project End
2010-06-30
Budget Start
2005-09-01
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$311,805
Indirect Cost
Name
New York University
Department
Neurology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Yang, Jing; Ji, Yong; Mehta, Pankaj et al. (2011) Blocking the apolipoprotein E/amyloid-? interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. J Alzheimers Dis 24:269-85
Zhang, Wei; Li, Yong-Sheng; Nardi, Michael A et al. (2010) Dissolution of arterial platelet thrombi in vivo with a bifunctional platelet GPIIIa49-66 ligand which specifically targets the platelet thrombus. Blood 116:2336-44
Wisniewski, Thomas; Boutajangout, Allal (2010) Immunotherapeutic approaches for Alzheimer's disease in transgenic mouse models. Brain Struct Funct 214:201-18
Wisniewski, Thomas; Boutajangout, Allal (2010) Vaccination as a therapeutic approach to Alzheimer's disease. Mt Sinai J Med 77:17-31
Goni, Fernando; Prelli, Frances; Ji, Yong et al. (2010) Immunomodulation targeting abnormal protein conformation reduces pathology in a mouse model of Alzheimer's disease. PLoS One 5:e13391
Wisniewski, Thomas; Sigurdsson, Einar M (2010) Murine models of Alzheimer's disease and their use in developing immunotherapies. Biochim Biophys Acta 1802:847-59
Wisniewski, Thomas (2009) AD vaccines: conclusions and future directions. CNS Neurol Disord Drug Targets 8:160-6
Scholtzova, Henrieta; Kascsak, Richard J; Bates, Kristyn A et al. (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer's disease-related pathology. J Neurosci 29:1846-54
Wisniewski, Thomas; Konietzko, Uwe (2008) Amyloid-beta immunisation for Alzheimer's disease. Lancet Neurol 7:805-11
Scholtzova, Henrieta; Wadghiri, Youssef Z; Douadi, Moustafa et al. (2008) Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's-disease-model transgenic mice shown as by micromagnetic resonance imaging. J Neurosci Res 86:2784-91

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