. Neuroprotective natural antibodies to assemblies of amyloidogenic peptides decrease with normal aging and advancing Alzheimer's disease. Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):12145-50. PubMed.


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  1. This is certainly a fascinating observation that healthy young individuals have relatively high concentrations of these circulating antibodies and that their levels seem to decline with age and in AD. It is also important that immunization against Aβ causes a dramatic increase in the levels of these antibodies that recognize not only Aβ, but oligomeric states of unrelated amyloids like ABri and ADan. Since the immune response to amyloids is largely directed against patterns of amino acid side chains on the surfaces of the β-sheets that result from the simple, parallel, and in-register structure of amyloids, it is not surprising that that the antibodies would react with many amyloids because these patterns would be expected to be the same on any amyloid that has the same amino acid. It may be a little speculative, but the reason that these types of antibodies seem to be favored is that these structures are predominantly if not exclusively pathological and do not occur on globular proteins. The immune response to amyloid aggregates appears to be part of the T cell independent innate immunity where B cells are already primed to respond to these antigens. This is like the innate immune response to things like bacterial cell walls and it seems to indicate that evolution has selected these antibodies because they are commonly encountered and the body needs to respond immediately to these threats.

    The results are consistent with some of our recent findings. Since the antibodies recognize generic, common epitopes, the converse prediction is that it doesn't really matter what peptide sequence you use to form amyloid: you will get the same immune response. We showed this is the case for Aβ and islet amyloid polypeptide (see Kayed et al., 2007). We recently extended this to even random peptide sequences that have no more than a four-amino-acid match in the entire human genome (Rasool and Glabe, 2008) and we showed that vaccination with this random sequence or IAPP gives the same therapeutic benefit in transgenic mice (Tg2576). We have also looked at passive immunization with conformation-dependent, oligomer-specific monoclonals and found that they improve cognition and prevent amyloid pathology in Tg2576 and 3XTg-Ag mice.

    The implications of these observations are that it may be possible to develop an effective human vaccine using random peptide sequences that form amyloid oligomers and that this vaccine would avoid the autoinflammatory side effects that doomed earlier vaccines. Even if there is a cytotoxic T cell response to the linear peptide, there is no protein in the human genome that displays this epitope for the T cells to attack, so vaccination against this antigen should have no more consequences than diphtheria toxin or pertussis, against which we vaccinate infants.

    Disclosure: The author has a financial interest in a company that is trying to develop oligomer-specific, conformation dependent antibodies that recognize generic, sequence independent epitopes on the surfaces of amyloid oligomers. This company is Kinexis Inc. of Carlsbad, CA.


    . Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is absent in prefibrillar oligomers. Mol Neurodegener. 2007;2:18. PubMed.

  2. This is state-of-the-art technology measuring sizable cohorts of human samples and fairly conclusively answers a question that was controversial in the literature regarding the levels of anti-Aβ antibodies in AD versus control samples.

    My take-home messages from the paper are the following:

    1. Titers against Aβ in unvaccinated human plasma are low. The dilution studies show titers of 1:50 to 1:200. Figure 3A shows that the antibody reactivity to Pneumococcal vaccine and Candida albicans are 100-1,000-fold greater than any of the anti-Aβ reactivities. The studies in nonhuman primates show that efficacious vaccines cause several hundredfold increases over non-immunized reactivities (Fig. 3E). Hock et al., although using a considerably different method, show titers greater that 1:10,000 in some vaccinated AD patients (see Hock et al., 2002). Hence, although these antibody titers may be "abundant," they are lower than the levels normally needed to be therapeutic.

    2. Figure 2D shows that roughly 75 percent of the antibodies against Aβ are masked by bound antigen. The declines seen with age in the plasma samples are diminished after unmasking the antibodies (dissociating bound antigen), implying the aging and AD effects observed may be secondary to increased amounts of antigen binding a greater fraction of the available antibodies in addition to, or instead of, reduced antibody levels.

    3. The neuroprotection data are intriguing, but it should be noted this activity requires purification of IgG and concentration of the IgG relative to that found in plasma. It sees unlikely the titers in plasma are sufficient to provide neuroprotection in vitro without this concentration.

    4. One critical missing piece of information regards the apparent affinity of the anti-Aβ antibodies for the antigens. When we did our work on dissociation of antigen-antibody complexes, we discovered a low-affinity/high-capacity binding artifact associated with antibodies that bound to the highly hydrophobic domains of Aβ with affinities (IC50s, in reality) greater than 10 μM (measured by competition with free Aβ), while the anti-Aβ antibodies generated by vaccination had IC50s of 1 μM for free Aβ, or less. Although the only definitive manner of addressing affinity is specific plasmon resonance, these competition studies can still reveal relative affinity. If these antibody activities in human plasma, which react more with the more hydrophobic variants of Aβ, are not effectively competed by preincubation with10-100 μM of the Aβ preparations used in the array, it seems unlikely these would have much impact on brain in vivo.

    In conclusion, this manuscript applies contemporary methods to a vexing problem regarding endogenous antibody titers against the Aβ peptide in humans. The general conclusions are that these titers are relatively low and considerably below those levels found therapeutic in mice, monkeys, and, apparently, humans. The authors conclude, and I concur, that these anti-Aβ activities are most likely derived by cross-reaction from antibodies directed against other antigens to which humans are commonly exposed. In any event, the question becomes, Does a lifetime of exposure to low levels provide some protection? My general impression is that it seems unlikely, but the authors’ conclusion that these could play a role in disease onset and progression is certainly one that merits further analysis and testing.


    . Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease. Nat Med. 2002 Nov;8(11):1270-5. PubMed.

  3. The Britshgi et al. paper nicely confirms our 2005 study (Moir et al., 2005) in which we measured titers of autoantibodies to "low molecular weight oligomeric cross-linked amyloid protein species (CAPS)," which we have long considered to be the neurotoxic form of Aβ in AD. We analyzed titers in AD and non-demented control plasma. While plasma of both non-demented and AD patients were found to contain autoantibodies specific for soluble CAPS, anti-CAPS antibodies in AD plasma were found to be significantly reduced compared with non-demented controls (p = 0.018). Furthermore, age at onset for AD correlated significantly (p = 0.041) with plasma immunoreactivity to CAPS. Based on these data, we suggested that autoantibodies to CAPS are depleted in AD patients and raised the prospect that immunization with anti-CAPS antibodies might provide therapeutic benefit for AD. The new study elegantly confirms and extends our earlier findings. Collectively, these findings reinforce the hypothesis that naturally occurring protective autoantibodies to toxic forms of Aβ exist in plasma and are depleted in AD.


    . Autoantibodies to redox-modified oligomeric Abeta are attenuated in the plasma of Alzheimer's disease patients. J Biol Chem. 2005 Apr 29;280(17):17458-63. PubMed.