The recent success of anti-amyloid-beta (A-beta) vaccination in transgenic (Tg), Alzheimer's disease (AD) model mice opens a new avenue for the potential treatment of AD. The therapeutic effect of the vaccine is thought to be mediated via an increased clearance of A-beta in the CNS and/or the circulation through an antibody mediated effect. The combination of native A-beta 1-42 and Freund adjuvant used by Schenk et al. is not feasible for the use in humans because of potential toxicity of both elements. It is well documented that A-beta 1-42 forms toxic fibrils and can cross the blood-brain barrier (BBB). This raised the possibility of toxicity in AD subjects. In this research proposal we suggest use of A-beta homologues peptides which are non-fibrillogenic and non-toxic but are able to elicit an immune response toward A-beta. Our preliminary data show that immunization with these peptides produces a reduction of A-beta deposits by 89% in APP Tg mice. In addition, as an alternative to Freund adjuvant, which is too toxic for human use, we propose to use non-toxic, aluminum based adjuvants (which are approved for human use). An alternative way of triggering immune response, which we will also test in this project will be intranasal administration of antigen. The vaccination approach is likely to work best in subjects who are in preclinical stages of AD. Therefore, there is increasing need to develop a technique allowing for the selection of susceptible individuals in the earliest stages of AD. Results of our preliminary studies indicates that native A-beta bound to gadolinium co-injected with mannitol or putrescine modified A-beta bound to gadolinium can cross the BBB and act as a contrast agent for amyloid lesions, making them detectable by magnetic resonance imaging. We are planning to employ these novel techniques in conjunction with behavioral testing to follow the effect of vaccination on Tg mice. Moreover, we would like to further develop this MRI-based technique to reduce the potential toxicity in order to make it applicable for use on human subjects.
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| Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta et al. (2004) Amyloid-beta deposition is associated with decreased hippocampal glucose metabolism and spatial memory impairment in APP/PS1 mice. J Neuropathol Exp Neurol 63:418-28 |
| Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta et al. (2004) A synthetic peptide blocking the apolipoprotein E/beta-amyloid binding mitigates beta-amyloid toxicity and fibril formation in vitro and reduces beta-amyloid plaques in transgenic mice. Am J Pathol 165:937-48 |
| Sadowski, Marcin; Pankiewicz, Joanna; Scholtzova, Henrieta et al. (2004) Targeting prion amyloid deposits in vivo. J Neuropathol Exp Neurol 63:775-84 |
| Sadowski, Marcin; Wisniewski, Thomas (2004) Vaccines for conformational disorders. Expert Rev Vaccines 3:279-90 |
| Sadowski, Marcin; Tang, Cheuk Ying; Aguinaldo, Juan Gilberto et al. (2003) In vivo micro magnetic resonance imaging signal changes in scrapie infected mice. Neurosci Lett 345:1-4 |
