Transcutaneous β-amyloid immunization reduces cerebral β-amyloid deposits without T cell infiltration and microhemorrhage

Department of Psychiatry and Behavioral Medicine, University of South Florida, Tampa, FL 33613, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2007; 104(7):2507-12. DOI: 10.1073/pnas.0609377104
Source: PubMed


Alzheimer's disease (AD) immunotherapy accomplished by vaccination with beta-amyloid (Abeta) peptide has proved efficacious in AD mouse models. However, "active" Abeta vaccination strategies for the treatment of cerebral amyloidosis without concurrent induction of detrimental side effects are lacking. We have developed a transcutaneous (t.c.) Abeta vaccination approach and evaluated efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage, in WT mice and a transgenic mouse model of AD. We demonstrate that t.c. immunization of WT mice with aggregated Abeta(1-42) plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta(1-42)-specific splenocyte immune responses. Confocal microscopy of the t.c. immunization site revealed Langerhans cells in areas of the skin containing the Abeta(1-42) immunogen, suggesting that these unique innate immune cells participate in Abeta(1-42) antigen processing. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Abeta(1-42) peptide plus CT. Similar to WT mice, PSAPP mice showed high Abeta antibody titers. Most importantly, t.c. immunization with Abeta(1-42) plus CT resulted in significant decreases in cerebral Abeta(1-40,42) levels coincident with increased circulating levels of Abeta(1-40,42), suggesting brain-to-blood efflux of Abeta. Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.


Available from: Jared Ehrhart
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    • "Several experimental immunizations, in animal models, are also utilizing the skin and nasal mucosa to deliver β amyloid. Nikolic et al. (2007) demonstrated that transcutaneous immunization with aggregated β amyloid peptide with adjuvant cholera toxin, lead to high titers of Aβ antibodies and lead to significant decreases in cerebral amyloid β levels. Other experiments show that Aβ derived peptides, with an adjuvant, delivered intranasally to mucosal epithelial tissues results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD (Maier et al., 2005, 2006). "
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    Frontiers in Neurology 01/2012; 3:5. DOI:10.3389/fneur.2012.00005
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    • "Nikolic et al. [101] APP/PSEN1dE9 "
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