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(American Journal of Pathology. 2006;169:738-739.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060633

Commentary

Amyloid-ß Vaccination: Testing the Amyloid Hypothesis?

Heads We Win, Tails You Lose!

Hyoung-gon Lee*, Xiongwei Zhu*, Akihiko Nunomura{dagger}, George Perry*{ddagger} and Mark A. Smith*

From the Department of Pathology,* Case Western Reserve University, Cleveland, Ohio; Department of Psychiatry and Neurology,{dagger} Asahikawa Medical College, Asahikawa, Japan; and College of Sciences,{ddagger} University of Texas at San Antonio, San Antonio, Texas

The goal of science, at its most fundamental level, is to construct hypotheses and thereafter to devise experiments that either disprove the hypothesis or, by not disproving it, provide additional support for the hypothesis. In the field of Alzheimer’s disease (AD), the predominant hypothesis is the Amyloid Cascade Hypothesis, the original version of which posited that insoluble fibrillar amyloid ß (Aß) is central to disease pathogenesis.1 In support of this hypothesis, Aß fibrils have been found to be toxic in vitro,2 and, since then, considerable effort has been and continues to be made on developing therapeutic modalities that target Aß fibrils. In this regard, transgenic mice that overexpress mutant forms of the Aß protein precursor (AßPP) and develop extensive fibrillar Aß-senile plaque deposits3 have become invaluable, despite the fact that such mice do not provoke neurodegeneration or other features of AD, which would seem to disprove the hypothesis. That withstanding, such transgenic mice have become important screening tools for potential therapeutics, and of the many agents found to "treat" these mice (ie, reduce Aß plaque deposits and rescue cognitive deficits), none has raised as much enthusiasm and expectations as the vaccination strategy.4,5

Around the same time that the vaccination approach was entering into human clinical trials, the original Amyloid Cascade Hypothesis1 underwent a slight modification in which the emphasis switched to oligomeric, rather than fibrillar, forms of Aß.6 Today, oligomeric Aß is viewed, almost universally in the field, as the most toxic and, therefore, most important species.7 What impact did this have for the clinical trial that targeted fibrillar amyloid? Before this question was answered, the clinical trial was suspended because of the development of encephalitis in a small percentage of individuals, an event that was subsequently blamed on the adjuvant.8 However, two alternate explanations may be more relevant in explaining such an unexpected outcome. First, while initial studies in mice supported vaccination-mediated decreases in both fibrillar and oligomeric species,4 the paper in this issue of The American Journal of Pathology9 shows that oligomeric amyloid may, in fact, increase in human patients who received the vaccination (Figure 1) . Specifically, while senile plaques were disaggregated in AD patients who received the vaccination, the amount of soluble amyloid was substantially increased when compared with nonvaccinated AD patients. Based on these findings, the authors suggest that the elevated pool of soluble amyloid may further impair neuronal function, reduce neural transmission, and promote neuroinflammation.9 In our opinion, such neuroinflammation may be a potential cause of the negative outcome of vaccination in some patients (ie, encephalitis). While the results of a related trial involving passive vaccination, to avoid adjuvant issues, are eagerly anticipated, the present findings essentially remove any "doubt" (sic) that amyloid is indeed responsible for AD. Simply, if patient health improves, it is because Aß fibrils are removed. On the other hand, if patients fare worse, it is because of increases in oligomeric Aß. Success or failure will equally support the Amyloid Hypothesis. However, as cited, in subgroup analysis, a percentage of patients may have benefited from the vaccination.10,11 Perhaps in such patients, clearance mechanisms enable rapid removal of Aß oligomers, with the benefit lying in removal of fibrils. Thus, the question now becomes explaining this finding so future therapeutic efforts can be more successful. Such investigations are no doubt pending. Nonetheless, this vaccination strategy does result in an increase in soluble (oligomeric?) amyloid in some people, and this would be viewed as detrimental according to the current construct of the Amyloid Cascade Hypothesis.


Figure 1
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  		Figure 1. In both human AD and transgenic models of AD, amyloid Aß is in dynamic equilibrium between soluble monomeric and soluble oligomeric forms and between soluble oligomeric and fibrillar forms. According to the two versions of the Amyloid Cascade Hypothesis, either fibrillar or oligomeric forms are viewed as toxic. Vaccination in transgenic animals shifts both equilibria to the left, resulting in decreases in both fibrillar and oligomeric forms of the protein. In contrast, in human patients with AD, vaccination may only shift the equilibria of fibrillar to oligomeric but not that between oligomeric and soluble forms. This could be detrimental (increase in oligomers) or beneficial (removal of fibrils) dependent on the version of the Amyloid Cascade Hypothesis under consideration.

 
While the two mainline amyloid theories consider amyloid as toxic, a second alternate role for Aß in AD must also be considered. We predicted originally that vaccination strategies were likely to fail,12,13 not because of an increase in oligomeric amyloid, but because we suspect that Aß is a protective consequence of the disease, not a cause of disease.14,15 Our Alternate Amyloid Hypothesis16 posits that Aß serves as a protective antioxidant and that its removal will exacerbate, rather than treat, disease. The paper by Roher and colleagues9 in this issue of the AJP gives us pause for thought on our original prediction12,13 —perhaps, by increasing oligomeric Aß, the vaccination strategy may work by increasing protective Aß. In other words, for both the Amyloid Cascade Hypothesis and the Alternate Amyloid Cascade, the results of the immunization trial are the same: Heads we win, tails you lose!

Footnotes

Address reprint requests to Mark A. Smith, Department of Pathology, 2103 Cornell Rd., Cleveland, OH 44106. E-mail: mark.smith{at}case.edu

This commentary relates to Patton et al, Am J Pathol 2006, 169:1048-1063, published in this issue.

Related Article on Page 1048

Accepted for publication June 28, 2006.

References

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  3. Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G: Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996, 274:99-102[Abstract/Free Full Text]
  4. 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: Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999, 400:173-177[CrossRef][Medline]
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  6. Hardy J, Selkoe DJ: The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002, 297:353-356[Abstract/Free Full Text]
  7. Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH: A specific amyloid-beta protein assembly in the brain impairs memory. Nature 2006, 440:352-357[CrossRef][Medline]
  8. Birmingham K, Frantz S: Set back to Alzheimer vaccine studies. Nat Med 2002, 8:199-200[Medline]
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  16. Lee HG, Zhu X, Nunomura A, Perry G, Smith MA: Amyloid beta: the alternate hypothesis. Curr Alzheimer Res 2006, 3:75-80[CrossRef][Medline]




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