: Alzheimer's disease (AD) is a major neurodegenerative disease for which there is currently no effective prevention or treatment. Amyloid-beta protein (Abeta) accumulation and accompanying inflammation appear to play key roles in initiating the pathogenesis of the neuronal degeneration that underlies the symptoms of AD. Reducing Abeta levels and/or its associated inflammation may delay or prevent the onset of the disease. Recent reports by several research groups, including ours, have shown that Abeta vaccination lowers cerebral Abeta in transgenic mice and can result in improved behavior. We hypothesize that chronic mucosal Abeta immunization with Abeta plus mucosal adjuvants induces a specific and sustained anti-Abeta response that, via clearance through Fc(gamma)-receptors and/or complement receptors, strongly lowers Abeta burden, resulting in reduced inflammation and neuronal degeneration. The central goal of this proposal is to advance this hypothesis in preparation for application to humans.
Our Specific Aims are: 1) to systematically determine the optimal immunization protocol for an effective mucosal (oral or nasal), transcutaneous, or combined (e.g., parenteral, then nasal) Abeta vaccine in wildtype (non-transgenic) mice, using various adjuvants, Abeta peptides and dosing schedules; 2) to determine the effectiveness of our optimized Abeta immunization protocol (from Aim 1) in each of 3 transgenic mouse models (APP, PS 1 and PSAPP) as well as for reduction of AA amyloid in a chemically- or genetically-induced mouse model of systemic AA amyloidosis; 3) to study the mechanism of Abeta immunization in vivo by assessing the role of complement, complement receptors (CR1 and CR3) and Fc(gamma)-receptors in Abeta reduction following immunization by immunizing (with our optimized protocol from Aim 1) APP transgenic mice crossbred with mice genetically deficient for either Clq, C3 or the Fc(gamma)-receptors RI and RIII. Our plan utilizes multiple routes of immunization, a diverse range of adjuvants and multiple mouse models, including 3 lines of Abeta-overproducing transgenic mice (APP, PS 1, PSAPP), mice with systemic AA amyloidosis, and 3 knockout mice lines (Clq-/-, C3-/- and Fc(gamma)R-/-). Multiple outcome measures will determine the effects of Abeta immunization on humoral and cell-mediated responses, as well as on cerebral Abeta burden and its associated inflammation. We believe our validated nasal mucosal immunization approach represents a unique and efficacious route for Abeta vaccination that could be convenient and well-tolerated, and thus provide a highly attractive method for prevention and treatment of AD in aged humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020159-02
Application #
6532582
Study Section
Special Emphasis Panel (ZAG1-PCR-5 (O4))
Program Officer
Snyder, Stephen D
Project Start
2001-09-30
Project End
2006-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$420,011
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Frost, Jeffrey L; Liu, Bin; Rahfeld, Jens-Ulrich et al. (2015) An anti-pyroglutamate-3 A? vaccine reduces plaques and improves cognition in APPswe/PS1?E9 mice. Neurobiol Aging 36:3187-3199
Liu, Bin; Frost, Jeffrey L; Sun, Jing et al. (2013) MER5101, a novel A?1-15:DT conjugate vaccine, generates a robust anti-A? antibody response and attenuates A? pathology and cognitive deficits in APPswe/PS1?E9 transgenic mice. J Neurosci 33:7027-37
Frost, Jeffrey L; Le, Kevin X; Cynis, Holger et al. (2013) Pyroglutamate-3 amyloid-? deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models. Am J Pathol 183:369-81
Fu, Hongjun; Liu, Bin; Frost, Jeffrey L et al. (2012) Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar A? by microglia. Glia 60:993-1003
Fu, H J; Liu, B; Frost, J L et al. (2010) Amyloid-beta immunotherapy for Alzheimer's disease. CNS Neurol Disord Drug Targets 9:197-206
Lemere, Cynthia A; Masliah, Eliezer (2010) Can Alzheimer disease be prevented by amyloid-beta immunotherapy? Nat Rev Neurol 6:108-19
Lemere, Cynthia A (2009) Developing novel immunogens for a safe and effective Alzheimer's disease vaccine. Prog Brain Res 175:83-93
Shankar, Ganesh M; Leissring, Malcolm A; Adame, Anthony et al. (2009) Biochemical and immunohistochemical analysis of an Alzheimer's disease mouse model reveals the presence of multiple cerebral Abeta assembly forms throughout life. Neurobiol Dis 36:293-302
Maier, Marcel; Peng, Ying; Jiang, Liying et al. (2008) Complement C3 deficiency leads to accelerated amyloid beta plaque deposition and neurodegeneration and modulation of the microglia/macrophage phenotype in amyloid precursor protein transgenic mice. J Neurosci 28:6333-41
Lemere, Cynthia A; Maier, Marcel; Peng, Ying et al. (2007) Novel Abeta immunogens: is shorter better? Curr Alzheimer Res 4:427-36

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