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The second generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects

Wiessner, Christoph and Wiederhold, Karl-Heinz and Tissot, Alain C and Frey, Peter and Danner, Simone and Jacobson, Laura and Jennings, Gary T and Lueoend, Rainer Martin and Ortmann, Rainer and Reichwald, Julia and Zurini, Mauro and Mir, Anis Khusro and Bachmann, Martin F and Staufenbiel, Matthias (2011) The second generation active Aβ immunotherapy CAD106 reduces amyloid accumulation in APP transgenic mice while minimizing potential side effects. The Journal of Neuroscience, 31 (25). pp. 9323-9331. ISSN 0270-6474

Abstract

Immunization against Aβ can reduce amyloid accumulation in vivo and is considered a potential therapeutic approach for Alzheimer’s disease. However, it has been associated with meningoencephalitis thought to be mediated by inflammatory T cells. With the aim of producing an immunogenic vaccine without this side effect we designed CAD106 comprising Aβ1-6 coupled to the virus-like particle Qβ. Immunization with this vaccine did not activate Aβ-specific T cells. In APP transgenic mice CAD106 induced efficacious Aβ antibody titers of different IgG subclasses mainly recognizing the Aβ3-6 epitope. CAD106 reduced brain amyloid accumulation in two APP transgenic mouse lines. Plaque number was a more sensitive readout than plaque area followed by Aβ42 and Aβ40 levels. Studies with very strong overall amyloid reduction showed an increase in vascular Aβ, which atypically was non-fibrillar. The efficacy of Aβ immunotherapy depended on the Aβ levels and thus differed between animal models, brain regions and stage of amyloid deposition. Therefore, outcomes from animal studies may not be quantitatively applicable to human AD. Our studies provided no evidence for increased microhemorrhages or inflammatory reactions in amyloid-containing brain. In Rhesus monkeys CAD106 induced a similar antibody response as in mice. The antibodies stained amyloid deposits on tissue sections of mouse and human brain but did not label cellular structures containing APP. They reacted with Aβ mono- and oligomers and blocked Aβ toxicity in cell culture. We conclude that CAD106 immunization is suited to interfere with Aβ aggregation and its downstream detrimental effects.

Item Type: Article
Related URLs:
Additional Information: Research publication of CAD106 requested by the GPT
Keywords: Alzheimer’s disease, amyloid, immunization, microhemorrhage, T cells, vascular
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/3885

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