Alzheimer's Disease (AD) pathogenesis has been linked to the abnormal processing of amyloid precursor protein (APP) resulting in excessive extracellular accumulation of Abeta peptide within plaque. In a pathogenic state Abeta entry into plaque must exceed its rate of removal. Peripheral vaccination with aggregated Abeta elicits an immune response resulting in reduction of apparent central nervous system amyloid by a mechanism that is presumed to involve CNS entry of antibodies and in situ removal from plaque. Humoral immunity has been implicated in this protective response, as some believe peripherally derived Abeta-specific antibodies act by altering Abeta equilibrium between the CNS and periphery thus preventing CNS deposition. The contribution of each of these processes may be a function of the type of antibody and its antigenic recognition properties. We hypothesize that immunization with forms of Abeta which undergo progressively enhanced degrees of fibrillarization will elicit immune responses against toxic higher-order Abeta structural intermediates that, in turn, will engender differential protection against disease pathogenesis. This application proposes to use a potent herpes virus-based vaccine strategy to determine the role of Abeta fibril formation in elicitation of strong anti-Abeta immune responses and how such host responses disrupt disease processes.
Three aims are proposed. Characterization of fibrillar and non-fibrillar Abeta peptide-expressing; amplicon-based vectors. Amplicons encoding the wild-type sequence for Abeta1-40 will be constructed along with vectors encoding mutated forms of Abeta shown previously to more readily form fibrillar structures. All vectors will be assessed in vitro for expression, antigen presentation, transgene product fibrillarization, and transgene product cytotoxicity profiles. Assessment of amplicon vectors in C57BL/6J mice. In vivo analyses of these vectors in C57BL/6J mice will be undertaken, including the profile of humoral and cellular immune responses as well as any untoward effects Abeta immunization may impart on behavior in normal mice. Assessment of immunization strategy in murine models of AD: Amplicon vectors will be administered to Sw C57BL/6J, SwDI C57BL/6J, and Tg2576 C57BL//6J mice to examine efficacy of the approach. Abeta burden, levels, and effects on CNS in these mice will be assessed using immunological, biochemical, and behavioral methods. Overall, these studies will elucidate the role of fibrillarization in the genesis of disease and establish the utility of amplicon-based vaccination for AD.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020204-03
Application #
6908099
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Buckholtz, Neil
Project Start
2003-09-30
Project End
2007-07-31
Budget Start
2005-08-01
Budget End
2006-07-31
Support Year
3
Fiscal Year
2005
Total Cost
$381,938
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Ryan, Deborah A; Federoff, Howard J (2009) Immune responses to herpesviral vectors. Hum Gene Ther 20:434-41
Sudol, Kelly L; Mastrangelo, Michael A; Narrow, Wade C et al. (2009) Generating differentially targeted amyloid-beta specific intrabodies as a passive vaccination strategy for Alzheimer's disease. Mol Ther 17:2031-40
Chiu, Yahui Grace; Bowers, William J; Lim, Seung T et al. (2009) Effects of herpes simplex virus amplicon transduction on murine dendritic cells. Hum Gene Ther 20:442-52
Janelsins, Michelle C; Mastrangelo, Michael A; Park, Keigan M et al. (2008) Chronic neuron-specific tumor necrosis factor-alpha expression enhances the local inflammatory environment ultimately leading to neuronal death in 3xTg-AD mice. Am J Pathol 173:1768-82
Bowers, William J; Mastrangelo, Michael A; Stanley, Hilary A et al. (2005) HSV amplicon-mediated Abeta vaccination in Tg2576 mice: differential antigen-specific immune responses. Neurobiol Aging 26:393-407