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SAGE KE Bulletin Board

Development of anti A-beta oligomeric antibodies, the next stage in the anti A-beta immunotherapy

16 December 2005

Estibaliz Capetillo-Zarate

Immunization with anti amyloid beta (A-beta) antibodies reduces A- beta deposition and improves cognitive function (Schenk et al., 1999) but encephalitis (Senior, 2002; Nicoll et al., 2003) and haemorrhage have been seen as side effects of A-beta immunization (Pfeifer et al., 2002; Racke et al., 2005).

To avoid these side effects new immunization strategies are in development. Several studies with immunogens against the truncated A-beta 1-15 peptide that contains the B cell epitope but lacks T cell reactive site of full length A-beta 1-42 and antibodies against A-beta oligomers were presented at the 34th SfN Annual Meeting 2005. Immunization with these compounds lead to behavioural improvement in APP transgenic mice (Maier et al. (2005); Jiang et al. (2005)). Lemere et al. also developed a dendrimeric A-beta 1-15 vaccine that administrated together with adjuvant LT(R192G) reduced plaque deposition, gliosis and neuritic dystrophies. Ma et al. showed that immunization with anti A-beta antibodies directed against oligomerimers of A-beta 1-15 reduced several different oligomeric forms of A-beta but not insoluble forms in Tg2576 transgenic mice. The reduction of A-beta correlated significantly with that of GSK-3-beta activity, a major tau kinase. These results were confirmed with an antibody that recognized oligomeric A-beta but does not recognized monomer or plaque amyloid. Reduction of phosphorilated tau after A-beta immunization strongly indicates that A-beta may lead the tangle formation and that specific anti A-beta oligomeric antibodies become very important in the development of the therapy. In summary, the development of antibodies avoiding T-cell activation may be an important step in establishing the appropriate tools for successful anti A-beta immunotherapy for AD pathology. Anti A-beta oligomeric antibodies, thereby, seem to be ideally suited to fulfil these criteria since they do not react with monomeric forms of A-beta.

References:

- L.Jiang, T.J.Seabrook, M.Maier, G.Bitan, C.A.Lemere. A prime/boost A vaccine using A 1 - 40/42 and dendrimeric A 1 - 15 peptide in APP tg mice. Program No. 544.3. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.

- C.A.Lemere, M.Maier, L.Jiang, G.Bitan, T.J.Seabrook. Dendrimeric A 1 - 15 intranasal immunization attenuates cerebral A while avoiding an A - specific cellular immune response in J20 APP transgenic mice. Program No. 703.7. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.

- Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO (2003) Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med 9:448-452.

- Q.Ma, G.P.Lim, M.E.Harris-White, F.Yang, A.S.Surendra, O.J.Ubeda, W.Beech, B.Teter, R.Kayed, C.G.Glabe, S.A.Frautschy, G.G.Cole. Antibodies against - amyloid rapidly reduce A oligomers and inhibit GSK - 3-beta activation and tau phosphorylation in vivo and in vitro. Program No. 325.7. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.

- M.Maier, T.J.Seabrook, L.Jiang, C.A.Lemere. Immunization with tandem - repeat A 1 - 15 peptides results in an effective humoral response and reduced cerebral A levels in the absence of a cellular response to full - length A in APP tg mice. Program No. 325.2. 2005 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience.

- Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M (2002) Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science 298:1379.

- Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan MT, Ness DK, Piroozi KS, Jordan WH, Brown DD, Hoffman WP, Holtzman DM, Bales KR, Gitter BD, May PC, Paul SM, DeMattos RB (2005) Exacerbation of cerebral amyloid angiopathy-associated microhemorrhage in amyloid precursor protein transgenic mice by immunotherapy is dependent on antibody recognition of deposited forms of amyloid beta. J Neurosci 25:629-636.

- Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Liao Z, Lieberburg I, Motter R, Mutter L, Soriano F, Shopp G, Vasquez N, Vandevert C, Walker S, Wogulis M, Yednock T, Games D, Seubert P (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173-177.

-Senior K (2002) Dosing in phase II trial of Alzheimer's vaccine suspended. Lancet Neurol 1:3.


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