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Good and Bad Amyloid Antibodies

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Science  26 Sep 2003:
Vol. 301, Issue 5641, pp. 1847-1849
DOI: 10.1126/science.301.5641.1847

Antibodies that recognize an oligomeric state common to different amyloidogenic proteins described by R. Kayed et al. (“Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” Reports, 18 Apr., p. 486) advance our understanding of Alzheimer's disease (AD) and other amyloid diseases, and provide a tool for probing such amyloid conformations in patients and in animal and cell culture models. Kayed et al. establish that the antibody they generated recognizes only oligomers of amyloid beta-peptides 1–40 and 1–42 (Aβ40 and Aβ42) that contain a minimum of eight peptide copies (octamers) and that it does not recognize amyloid fibrils. Previous studies had suggested that Aβ40 and Aβ42 are particularly toxic to cells when they are in an early stage of the peptide aggregation process (1, 2). The findings of Kayed et al. confirm and extend this notion by showing that the state-specific amyloid antibody inhibits the cytotoxicities of a range of amyloidogenic peptides, including those involved in prion disorders, Parkinson's and Huntington's diseases, and type II diabetes.

Efforts to develop a vaccine for AD based on immunization with Aβ42 or administration of Aβ antibodies (passive immunization) have encountered mixed results. Several laboratories have documented the clearance of Aβ aggregates from the brains of transgenic mice expressing mutant amyloid precursor protein, a mouse model of AD (3, 4). However, the mouse studies did not establish whether the Aβ antibodies produced by or given to the mice modified the neurotoxicity of the Aβ in the brains of the mice. In an initial clinical trial in which AD patients were administered Aβ to elicit an immune response, some of the patients appeared to be benefiting from the vaccine (5), but several patients developed encephalitis (6). Although Kayed et al. found that their antibody against oligomeric A was capable of protecting cultured cells against the toxicity of such forms of Aβ, we have found that several other Aβ antibodies potentiate the neurotoxicity of Aβ (7). Previous studies showed that Aβ generates reactive oxygen species, including hydrogen peroxide, only when the peptide is in an aggregating oligomeric form (8, 9). When the latter process occurs when Aβ is in contact with cell membranes, lipid peroxidation occurs, resulting in perturbed membrane transporter and ion channel functions that can lead to cell death (10).

Aβ antibodies might facilitate the formation of a toxic peptide conformation (7). However, the possibility that the interaction of the antibodies with Aβ catalyzes or enhances the generation of reactive oxygen species should also be considered. Lerner and colleagues (11, 12) have shown that many antibodies can convert molecular oxygen into hydrogen peroxide and short-lived hydroxylating radical species such as hydrotrioxy radical. When we tested several different Aβ antibodies to determine their ability to modify the amount of oxidative damage to cells induced by Aβ, some of the antibodies increased the damage, whereas others decreased the damage. Because many different Aβ antibodies are produced in response to immunization with Aβ, our findings suggest that some of the antibodies may exacerbate the neurodegenerative process. Passive immunization with Aβ antibodies with predetermined effects on Aβ clearance and toxicity might reduce or eliminate potentially serious side effects resulting from vaccination with Aβ.

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