. Immunization reverses memory deficits without reducing brain Abeta burden in Alzheimer's disease model. Nat Neurosci. 2002 May;5(5):452-7. PubMed.


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  1. "The findings by Dodart and colleagues are very interesting. However, as Steven Paul points out in the Q and A session on this website, it remains to be seen if a similar effect will be observed in other transgenic AβPP mouse models and eventually in AD patients. Reversal of behavioral deficits was not associated with reduction in amyloid plaque burden or alterations in levels of total brain Aβ, but was significant at doses that allowed detection of Aβ-antibody complexes in the CSF. However, levels of soluble brain Aβ or the presence of antibodies bound to plaques were not measured.

    Increase or Decrease of Soluble Aβ?
    The authors speculate that the behavioral improvements may be caused by efflux of soluble Aβ out of the brain. This may be true, but the reversal of memory deficits may as well be caused by a rapid increase in soluble Aβ within the CNS, derived from plaque Aβ. However, this acute increase may not be sufficient to significantly reduce plaque burden. This alternative explanation should come as no surprise as numerous laboratories have shown low levels of Aβ to have neurotrophic effects in cell culture, which may translate into a beneficial neuromodulatory effect in vivo. Follow-up studies measuring soluble Aβ within the brain should clarify this issue.

    It is certainly difficult to compare behavioral studies in various immunized transgenic AβPP models of different background strains. And yet, a treatment induced-increase in brain soluble Aβ may actually explain similarities within the reported behavioral studies, whereas Dodart et al. mention that their data seem to contrast with previous findings (Janus et al., 2000; Morgan et al., 2000). Janus et al. observed behavioral improvement associated with reduction in plaques but no change in total brain Aβ. Although they suggested that cognitive improvement might be due to reductions in potentially toxic protofibrils, it may also have been caused by an increase in soluble brain Aβ levels. Morgan et al. observed a partial reversal of cognitive deficits in AβPP/PS1 mice, though cerebral amyloid burden as measured by immunohistochemistry was not significantly reduced. The authors suggested that a decrease in soluble Aβ might explain the cognitive improvement in the immunized mice, but this potential connection was not measured in their study.

    Our results following 7 months of treatment suggest that the reduction in soluble brain Aβ is less than that of plaque Aβ (see related ARF news items), but we did not analyze the behavior of the mice. All the behavioral studies may fit nicely together if the cognitive improvements were caused by an increase in soluble Aβ within the CNS. This view may seem to contradict findings suggesting toxicity of soluble Aβ species (see news story), but we emphasize that the in-vivo ratio of Aβ monomers/oligomers and protofibrils/fibrils in transgenic mice and AD brain has not been thoroughly established, and any future biochemical findings will likely vary depending on the methods used. Furthermore, Aβ oligomers found in these mice may be less stable than those detected in AD brains (Kalback et al., 2002), and their toxicity has not been demonstrated. It is likely that most of the soluble Aβ in mouse brain are monomers, which may be trophic instead of toxic.

    Previously, these authors showed that peripheral injection of anti-Aβ antibody decreased brain amyloid burden without binding to amyloid plaques, but the presence of Aβ-antibody complexes was not measured in the CSF (see related ARF news items) While both these studies show an extensive increase in plasma Ab levels, they cannot be easily compared because of differences in parameters measured. The present results need to be replicated in other AβPP transgenic models. They also need to be correlated with levels of soluble brain Aβ, as well as amounts of various AβPP fragments that may affect behavior. In the PDAPP model, Aβ is predominantly generated within the CNS, whereas in the Tg2576 model Aβ is formed in various peripheral organs as well. It is, therefore, likely that any sequestration of Aβ from the CNS to the periphery will be greater in the PDAPP model, and a higher dose may be needed to achieve a similar effect in Tg2576 mice.

    The predictive value of the transgenic AβPP mouse models are questionable also because the plaques in the AβPP23 and the Tg2576 mouse models are much more soluble than those in AD, though vascular amyloid is as insoluble in these mice as in AD (Kuo et al., 2001; Kalback et al., 2002). This finding suggests that the mouse plaques may be more easily removed than those in AD. It may be explained by transgenic mice having fewer posttranslational modifications within the Aβ peptides, as well as by differences in the composition of amyloid-associated proteins. However, a contradicting finding in the Tg2576 model has been reported (Kawarabayashi et al., 2001), in which the portion of Aβ requiring formic acid for extraction showed an age-related increase and eventually reached similar levels as seen in AD brain. This controversy regarding the ratio of soluble versus insoluble Aβ in Tg mice needs to be resolved, and a similar study should be performed in the PDAPP model. Future therapy studies should also attempt to determine the ratio of various Aβ species.

    Overall, therapeutic findings in these mouse models must be interpreted cautiously, as they may not apply to the human condition. It should be noted, however, that although amyloid burden in AD patients and AβPP transgenic mice has been reported to be similar, human plasma Aβ levels are several-fold lower than those observed in the Tg2576 mice. Therefore, a smaller amount of antibodies per weight may be needed in humans than in transgenic mice to achieve similar therapeutic results, although we should not expect that antibodies will lead to clearance of existing plaques in AD brains, which postmortem require formic acid for solubilization."


    . A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):979-82. PubMed.

    . A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. PubMed.

    . APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques. Biochemistry. 2002 Jan 22;41(3):922-8. PubMed.

    . Comparative analysis of amyloid-beta chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer's disease brains. J Biol Chem. 2001 Apr 20;276(16):12991-8. PubMed.

    . Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci. 2001 Jan 15;21(2):372-81. PubMed.

    View all comments by Blas Frangione
  2. The remarkable finding described by Dodart et al. in Nature Neuroscience adds an important page to the evolving story of Aβ toxicity in Alzheimer's disease. It builds on two related discoveries. First, thanks to the pioneering work of Dale Schenk and colleagues (Schenk et al, 1999), we have known for three years that active and passive vaccination can have a major impact on brain chemistry, a terrifically surprising and important discovery. Schenk's original findings showed that vaccination with fibril-enriched preparations of Aβ could significantly lower amyloid plaques in transgenic mice models for AD. Second, since the work of Lambert et al., 1998, we've also known that small oligomers of Aβ, soluble and globular in structure, have potent CNS effects. The disruptive activity of oligomers (aka "ADDLs") is likely to account for the imperfect correlation between dementia and plaque burden in Alzheimer's disease.

    Particularly relevant to the study by Dodart et al, ADDLs rapidly inhibit LTP, a major paradigm for synaptic memory formation (Lambert, ibid, see also more recent works by Wang et al., 2002, and Walsh et al, 2002, (see related ARF news items). The fast and selective nature of LTP inhibition indicates that it is not a consequence of neuronal degeneration. Because these synaptic effects appear dysfunctional rather than degenerative, we have proposed that memory loss in AD (and in mild cognitive impairment) could actually be reversed, not just slowed down (see, e.g., Klein et al., 2001). As seen in Dodart et al., the rapid cognitive reversal in antibody-treated transgenic mice provides strong support for this hypothesis.

    Dodart's findings underscore the potential value in developing vaccines that target soluble toxins. The usefulness of such vaccines was suggested by earlier work from Morgan et al., 2000, who found that vaccination improved memory performance in transgenic mice whether or not plaques were eliminated. We might expect that ideal therapeutic antibodies would be able to discriminate between toxic oligomers and physiological monomers. Toxicity-neutralizing antibodies with such specificity recently have been generated by vaccination of rabbits with ADDLs (Lambert et al., 2001). Even greater specificity ultimately may be crucial. For example, vaccines that target soluble toxins but avoid insoluble amyloid deposits may circumvent the CNS inflammation recently uncovered in human clinical trials (see vaccination live chat).

    In a wider venue, recent evidence by Bucciantini et al. indicates that other protein misfolding diseases, previously associated with amyloid deposition, also may have pathogenic sub-fibrillar species (see related ARF news items). It is possible, therefore, that approaches developed for targeting such species in AD ultimately may have broad application.


    . Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999 Jul 8;400(6740):173-7. PubMed.

    . Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A. 1998 May 26;95(11):6448-53. PubMed.

    . Soluble oligomers of beta amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus. Brain Res. 2002 Jan 11;924(2):133-40. PubMed.

    . Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?. Trends Neurosci. 2001 Apr;24(4):219-24. PubMed.

    . A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. PubMed.

    . Vaccination with soluble Abeta oligomers generates toxicity-neutralizing antibodies. J Neurochem. 2001 Nov;79(3):595-605. PubMed.

    View all comments by William Klein
  3. This paper makes important advances in the immunization field on two fronts. First, it follows up on previous papers, such as that out of Dave Morgan's work, suggesting that the vaccine can reduce the cognitive deficit associated with the accumulation of Aβ, without removing the neuritic plaques. The reason is presumably that soluble Aβ oligomers and proto-fibrils are being reduced. Examples of such protofibrils are given in work on ADDLs by the work or Bill Klein and Grant Krafft. The current work confirms the observation that cognitive deficits can be improved without eliminating neuritic plaques, and focuses attention on the toxicity associated with soluble Aβ.

    A second reason that this work might be particularly important is because it furthers prior work by Steve Paul's group showing that administration of peripheral anti-Aβ can reduce plaque load, and now the cognitive deficit associated with plaque load. Given potential difficulties with the active immunization model, this passive immunization model takes on increased importance (although there is a possibility that the problems with the human trials of the Aβ vaccine were not directly due to the Abeta antibodies). One can imagine that humanized anti-Aβ antibodies might be useful clinically.

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