The immunological concept in the treatment of conformational diseases, such as Alzheimer’s, is based on antibody-antigen interactions involving conformational changes in both antibody and antigen. Appropriate mAbs interact at strategic sites where protein aggregation is initiated, stabilize the protein and prevent further aggregation. For such an active role, the mAbs require a high binding constant to the "strategic" positions on the antigen molecule (Solomon, 2002). The existence of strategic positions where conformational changes are initiated has been shown in model systems (Silen et al., 1989; Solomon et al., 1995), recently in Alzheimer’s Aβ peptide (Frenkel et al., 1998; Frenkel et al., 1999) and prion-related diseases (Peretz et...  Read more

The immunological concept in the treatment of conformational diseases, such as Alzheimer’s, is based on antibody-antigen interactions involving conformational changes in both antibody and antigen. Appropriate mAbs interact at strategic sites where protein aggregation is initiated, stabilize the protein and prevent further aggregation. For such an active role, the mAbs require a high binding constant to the "strategic" positions on the antigen molecule (Solomon, 2002). The existence of strategic positions where conformational changes are initiated has been shown in model systems (Silen et al., 1989; Solomon et al., 1995), recently in Alzheimer’s Aβ peptide (Frenkel et al., 1998; Frenkel et al., 1999) and prion-related diseases (Peretz et al., 2001; Hanan et al., 2001). The many authors of the Bard et al. paper show in a most convincing way that antibodies against the N-terminus of Aβ are effective in clearing amyloid plaques (Hanan et al., 1996; Solomon et al., 1997), thus partially avoiding the drawbacks related to immunization with whole Aβ1-42. At the same time, the study lacks the rationale regarding the minimal epitope of anti-aggregating antibodies.

Using a phage-peptide library composed of filamentous phage displaying three million random combinatorial peptides, we defined the EFRH residues located at positions 3-6 of the N-terminal Aβ as the epitope of anti-aggregating antibodies within Aβ (Frenkel et al., 1998; Frenkel et al., 1999). The EFRH is not only the epitope of anti-aggregating antibodies but acts as a regulatory site controlling both the formation and disaggregation process of the amyloid fibrils. Locking of this epitope by highly specific antibodies affects the dynamics of the entire Aβ molecule, preventing self-aggregation as well as enabling resolubilization of already formed aggregates. This conclusion was reached from experimental data with different lengths of Aβ peptides or similar peptides with one or two mutations in EFRH region (Frenkel et al., 1998; Frenkel et al., 1999).

Antibodies resulting from EFRH immunization are similar in their anti-aggregating properties to antibodies raised by direct injection with whole Aβ and/or mAbs directed to this region (Frenkel et al., 2000). Such antibodies at low titer (1-100—1-1000) are enough to reduce the amyloid plaques to the same extent as passive immunization with larger amounts of antibodies directed to EFRH (Frenkel et al., 2003). Antibodies that bind to the epitope containing only a few amino acids from EFRH, such as mAb 3D6 (Bacskai et al., 2002), are less effective compared to mAb 10D5, which binds to the whole sequence.

However, not all the antibodies that bind to EFRH exhibit anti-aggregating properties. Mab 2H3, whose epitope is located between amino acids 1-7, binds with a higher binding constant (10-⁹M) to the whole epitope, but only with (10-⁴M) to EFRH and did not have anti-aggregating properties, highlighting the importance of the high affinity of the antibodies to this specific sequence on the behavior of whole Aβ (Frenkel et al., 1999).

Unfortunately, immunization could have contradictory effects; besides disaggregating amyloid plaques it could trigger also microglial overactivation, which might lead to neuroinflammation. Mabs that bind to available epitopes of Aβ in brain (passive or active immunization) activate the Fc receptors which may initiate the inflammatory response. Modulation of FcR activation, using antibodies devoid of the Fc region, or partial FcR blockage, may be efficient practical therapeutic approaches for controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD (Solomon, 2002).

References:
Solomon B. Immunological concept in the treatment of Alzheimer’s disease. Drug Development Research. 2002;56:163-167. (No abstract available)

Silen JL, Agard DA. The alpha-lytic protease pro-region does not require a physical linkage to activate the protease domain in vivo. Nature. 1989 Oct 5;341(6241):462-4. Abstract

Solomon B, Schwartz F. Chaperone-like effect of monoclonal antibodies on refolding of heat-denatured carboxypeptidase A. J Mol Recognit. 1995 Jan-Apr;8(1-2):72-6. Abstract

Frenkel D, Balass M, Solomon B. N-terminal EFRH sequence of Alzheimer's beta-amyloid peptide represents the epitope of its anti-aggregating antibodies. J Neuroimmunol. 1998 Aug 1;88(1-2):85-90. Abstract

Frenkel D, Balass M, Katchalski-Katzir E, Solomon B. High affinity binding of monoclonal antibodies to the sequential epitope EFRH of beta-amyloid peptide is essential for modulation of fibrillar aggregation. J Neuroimmunol. 1999 Mar 1;95(1-2):136-42. Abstract

Peretz D. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001 Aug 16; 412(6848):739-43. Abstract

Hanan E, Goren O, Eshkenazy M, Solomon B. Immunomodulation of the human prion peptide 106-126 aggregation. Biochem Biophys Res Commun. 2001 Jan 12;280(1):115-20. Abstract

Hanan E and Solomon B. Protective effect of monoclonal antibodies against Alzheimer’s beta-amyloid aggregation. Amyloid: Int. J. Exp. Clin. Invest. 1996;3:130-133. (No abstract available)

Solomon B. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A. 1997 Apr 15. Abstract

Bacskai BJ. Non-Fc-mediated mechanisms are involved in clearance of amyloid-beta in vivo by immunotherapy. J Neurosci. 2002 Sep 15; 22(18):7873-8. Abstract

Frenkel D. Immunization against Alzheimer's beta -amyloid plaques via EFRH phage administration. Proc Natl Acad Sci U S A. 2000 Oct 10; 97(21):11455-9. Abstract

Frenkel D. Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization. Vaccine. 2003 Mar 7; 21(11-12):1060-5. Abstract

Solomon B. Immunological approaches as therapy for Alzheimer's disease. Expert Opin Biol Ther. 2002 Dec ; 2(8):907-17. Abstract

View all comments by Beka Solomon

This is a study on a quite impressive scale that compares different isotypes of anti-Abeta antibodies with respect to efficacy in attenuating amyloid loads in PDAPP mice. The conclusion is anti-Abeta IgG with high affinity for Fc receptors are more effective then those with lower affinity for FcR. This supports this group's hypothesis that microglial uptake of anti-Abeta:Abeta complexes is important in Abeta immunotherapy. Our group is currently preparing a manuscript that is not easily reconcilable with these findings. Our data has also been presented at recent meetings. We find that Abeta immunotherapy is equally effective in Tg2576 mice crossed into an FcR gamma knockout background mice as it is in wt Tg2576 mice. Our studies would seem to preclude FcR mediated uptake of anti-Abeta:Abeta complexes as a factor in determing efficacy of immunization. Although there was no good correlation between efficacy in the bard study and binding affinites of the antibodies to soluble or aggregated Abeta, perhaps there is some other property of the anibodies that is more closely...  Read more

This is a study on a quite impressive scale that compares different isotypes of anti-Abeta antibodies with respect to efficacy in attenuating amyloid loads in PDAPP mice. The conclusion is anti-Abeta IgG with high affinity for Fc receptors are more effective then those with lower affinity for FcR. This supports this group's hypothesis that microglial uptake of anti-Abeta:Abeta complexes is important in Abeta immunotherapy. Our group is currently preparing a manuscript that is not easily reconcilable with these findings. Our data has also been presented at recent meetings. We find that Abeta immunotherapy is equally effective in Tg2576 mice crossed into an FcR gamma knockout background mice as it is in wt Tg2576 mice. Our studies would seem to preclude FcR mediated uptake of anti-Abeta:Abeta complexes as a factor in determing efficacy of immunization. Although there was no good correlation between efficacy in the bard study and binding affinites of the antibodies to soluble or aggregated Abeta, perhaps there is some other property of the anibodies that is more closely associated with efficacy? For example binding to oligomers, ability to cross the blood brain barrier, etc....

View all comments by Todd E. Golde

This is a very exciting development for a rapidly fatal disease, for which there is no known therapy. Particularly important is that the passive immunotherapy can be started relatively late in the replication phase of the disease. While not identical, both Alzheimer's and prion disorders result in accumulations of fibrils of conformationally abnormal proteins that cause neurodegeneration. If immunotherapy shows any benefit in human prion disorders, it should encourage further development of immunotherapy for Alzheimer's patients. To my knowledge, this is the only therapy which appears to "cure" scrapie in mice.

View all comments by Dave Morgan

We are pleased that White and colleagues confirm our recent findings that anti-prion antibodies have the potential to be used as prophylaxes following scrapie exposure (Sigurdsson et al., 2002; Sigurdsson et al., 2003). We were surprised that they did not quote our 2003 study that was published before their paper was accepted. In addition, the editors of Nature were well aware of our work, as we submitted it to their journal in June 2002. Together, these in-vivo studies support previous in-vitro findings and results from transgenic mice expressing anti-prion antibodies, as referenced in our articles.

By administering 2 mg of anti-prion antibodies twice a week, White et al. achieved a substantially better therapeutic effect than we did by injecting 50 μg once a week. Although extrapolation of an effective dose in a mouse to a human dose is not an exact science, 2 mg/20 g mouse corresponds to a 6 g/60 kg individual. Hopefully, a...  Read more

We are pleased that White and colleagues confirm our recent findings that anti-prion antibodies have the potential to be used as prophylaxes following scrapie exposure (Sigurdsson et al., 2002; Sigurdsson et al., 2003). We were surprised that they did not quote our 2003 study that was published before their paper was accepted. In addition, the editors of Nature were well aware of our work, as we submitted it to their journal in June 2002. Together, these in-vivo studies support previous in-vitro findings and results from transgenic mice expressing anti-prion antibodies, as referenced in our articles.

By administering 2 mg of anti-prion antibodies twice a week, White et al. achieved a substantially better therapeutic effect than we did by injecting 50 μg once a week. Although extrapolation of an effective dose in a mouse to a human dose is not an exact science, 2 mg/20 g mouse corresponds to a 6 g/60 kg individual. Hopefully, a clinically effective prophylactic dose in humans will be closer to the dose we administered.

To avoid any misunderstanding, we would like to point out that in one of our effective treatment paradigms, we initiated active immunization 24 hours after scrapie infection (Sigurdsson et al., 2002). This would result in detectable anti-prion antibodies probably over a month following exposure. Although this rescue approach had a less dramatic effect than our prophylactic treatment, it cannot be interpreted as a simple neutralization of the inoculum, as stated in the White et al. paper. Rather, it indicates that the antibodies may in some way be interfering with PrP^Sc-mediated conversion of PrP^C to PrP^Sc, and/or increasing clearance of endogenous PrP^Sc.

View all comments by Blas Frangione

Having proof that established prion replication in the living situation can be controlled, there is no reason why these mouse monoclonal antibodies should not be humanized and infused into the brains of patients with human prion diseases.

View all comments by Simon Hawke

This an extremely interesting preliminary report. The editorial by Winblad and Blum is very careful in conveying both the excitement this data causes, and also the caution that needs to be exercised in its interpretation. Hock and his colleagues are to be congratulated for their astuteness in taking part in the Elan trial, but negotiating themselves some freedom in using their own data from their trial subjects. Let's hope that when Elan releases the data on the whole trial, the overall results confirm these preliminary data. Even if immunization turns out not to be the way forward for safety reasons, such an outcome would imply that other Aβ-reducing strategies have every chance of clinical success.

View all comments by John Hardy

It is encouraging that in a subset (n=30) of the more than 300 subjects enrolled in the Elan study who were analyzed, there is preliminary evidence that there may be a positive response. This preliminary analysis suggests that further, more conclusive studies of the immunization approach (active and passive) should continue. Though the analysis argues for more studies, the title and some of the conclusions of this study are not yet justified. As pointed out in the accompanying commentary by Winblad and Blum, the control group, which is really N=6 who received placebo or N=10 total who did not generate "antibodies," is very small. More importantly, not only is the control group small, that group deteriorated at a much faster rate than subjects with mild to moderate Alzheimer's disease normally worsen. The amount of MMSE decline in the group treated with immunization is actually what is described in patients with Alzheimer's who are on cholinesterase inhibitors, (which many of these patients were on), namely about one to three points in the first year of follow-up. It would have...  Read more

It is encouraging that in a subset (n=30) of the more than 300 subjects enrolled in the Elan study who were analyzed, there is preliminary evidence that there may be a positive response. This preliminary analysis suggests that further, more conclusive studies of the immunization approach (active and passive) should continue. Though the analysis argues for more studies, the title and some of the conclusions of this study are not yet justified. As pointed out in the accompanying commentary by Winblad and Blum, the control group, which is really N=6 who received placebo or N=10 total who did not generate "antibodies," is very small. More importantly, not only is the control group small, that group deteriorated at a much faster rate than subjects with mild to moderate Alzheimer's disease normally worsen. The amount of MMSE decline in the group treated with immunization is actually what is described in patients with Alzheimer's who are on cholinesterase inhibitors, (which many of these patients were on), namely about one to three points in the first year of follow-up. It would have been very useful if this study included all of the subjects in the Elan trial over the first year. One comment about the measurement of Aβ levels in plasma and CSF is warranted. The study measured Aβ by ELISA. If these subjects generated antibodies, they were polyclonal antibodies. These antibodies can bind to Aβ in the plasma (or CSF) and, if they are present, can potentially block binding of other antibodies used in the ELISA. No methods were used to account for this. Thus, the plasma and CSF Aβ levels are not interpretable with the technique used here. Also, there appears to be an error in Fig. 4B for CSF Aβ42. It is listed as ng/ml, but presumably is pg/ml. In the legend for Fig. 4, it appears A and B are reversed. In summary, while this clinical report is encouraging, it is preliminary.

View all comments by David Holtzman

Since this is a clinical study involving human subjects, one cannot expect it to be without unavoidable limitations. The numbers of patients are small, the follow-up is of relatively short duration, and these are both problems, as Winblad and Blum point out. The mental state of AD patients can fluctuate widely, so I think more specific functional tests will have to be done to strengthen the case for a positive effect.

Let's assume that some of the patients show improvement and this is correlated with antibody levels. Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Aβ? If these were experimental animals, one would be able to test the effects of immunizing with different forms of synthetic peptides. This is clearly not possible with human subjects. I am also concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay. It is possible that they are looking at different conformational epitopes, as the authors suggest, but one...  Read more

Since this is a clinical study involving human subjects, one cannot expect it to be without unavoidable limitations. The numbers of patients are small, the follow-up is of relatively short duration, and these are both problems, as Winblad and Blum point out. The mental state of AD patients can fluctuate widely, so I think more specific functional tests will have to be done to strengthen the case for a positive effect.

Let's assume that some of the patients show improvement and this is correlated with antibody levels. Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Aβ? If these were experimental animals, one would be able to test the effects of immunizing with different forms of synthetic peptides. This is clearly not possible with human subjects. I am also concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay. It is possible that they are looking at different conformational epitopes, as the authors suggest, but one should not overlook the fact that the tissue assay involves "fixed" tissue (they don't specify how) that is embedded in paraffin. It is not stated whether the Aβ peptides were similarly treated. If they were not, I would look first at the differences in antigenicity related to antigen preparation before concluding that conformational differences explain differences in immunoreactivity.

I find it puzzling that serum antibodies against Aβ remain high in the patients, without changes in circulating Aβ levels.

View all comments by Vincent Marchesi

This paper continues the rollercoaster of emotion regarding the use of amyloid vaccines to treat Alzheimer's disease. The identification that Aβ vaccination could dramatically reduce amyloid deposition in the PDAPP mouse (Schenk et al., 1999), followed by demonstration that the vaccine also protected mice from learning and memory deficits (Janus et al., 2000; Morgan et al., 2000), led to early trials of the vaccine in humans. Although Phase I trials found no adverse consequences, six percent of the Phase II trial patients developed aseptic meningoencephalitis (Schenk, 2002), which in some cases was severe (Nicoll et al., 2003). This led to premature termination of the trial, with cessation of any further inoculations with the Aβ...  Read more

This paper continues the rollercoaster of emotion regarding the use of amyloid vaccines to treat Alzheimer's disease. The identification that Aβ vaccination could dramatically reduce amyloid deposition in the PDAPP mouse (Schenk et al., 1999), followed by demonstration that the vaccine also protected mice from learning and memory deficits (Janus et al., 2000; Morgan et al., 2000), led to early trials of the vaccine in humans. Although Phase I trials found no adverse consequences, six percent of the Phase II trial patients developed aseptic meningoencephalitis (Schenk, 2002), which in some cases was severe (Nicoll et al., 2003). This led to premature termination of the trial, with cessation of any further inoculations with the Aβ peptide. Thus, as rapidly as hope was raised by the early successes in animal models, all the enthusiasm for the vaccine as a potential therapy crashed, leading some to accuse Elan of proceeding too rapidly into human trials in spite of the safety testing performed in Phase I. For the last year, very few grants were supported that proposed to investigate the amyloid vaccine, even if it was only used as a tool to reduce Aβ deposits. Several other reports appeared suggesting that Aβ vaccination would have adverse consequences, such as hemorrhage (Pfeifer et al., 2002) or invasion of T cells into the CNS (Furlan et al., 2003). It seemed increasingly unlikely that the scientific community could be convinced that anti-Aβ immunotherapy should continue to be investigated. Now, this manuscript by Hock et al., reporting on their subset of patients from the Elan clinical trial, shows (by some measures) a significant slowing of cognitive deterioration in those patients with plaque-reactive antibodies. Moreover, the patients with the highest antibody titers have remained stable or even improved their cognitive functions over a year's time. Thus, the immunotherapy rollercoaster begins another climb up the track. It has risen, phoenix-like, to again generate hope among the millions with relatives suffering from end-of-life dementias. It will be important in this swing of the pendulum to avoid hype and promotion, and to maintain a sober outlook while investigating the advantages and disadvantages of this approach to dementia therapy. At the AD-PD meeting in Seville in early May 2003, where the Hock et al. data were presented, the representatives from Elan were quick to point out that this is a subset of patients from their trial. They also indicated that, at least based upon intention to treat (i.e., comparing the group receiving the vaccine vs. placebo), there was no benefit in the ADAS-COG scores in the complete dataset. It remains to be determined if, overall, the subset of patients with plaque-reactive anti-Aβ antibodies do still show benefit from the vaccination. The 12-month decline in cognitive function in the group lacking anti-Aβ antibodies in the Hock et al. study is greater than is typically observed over this period (see commentary by Winblad). However, this report will once again encourage the investigation of anti-Aβ immunotherapy as a treatment for dementias, and will permit neuroscientists and immunologists to develop alternative methods of increasing anti-Aβ titers while avoiding meningoencephalitis and other potential problems associated with this once-again promising avenue of therapy.

References:
Furlan R, Brambilla E, Sanvito F, Roccatagliata L, Olivieri S, Bergami A, Pluchino S, Uccelli A, Comi G, Martino G. Vaccination with amyloid-beta peptide induces autoimmune encephalomyelitis in C57/BL6 mice. Brain. 2003 Feb;126(Pt 2):285-91. Abstract

Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y, Schmidt SD, Chishti MA, Horne P, Heslin D, French J, Mount HT, Nixon RA, Mercken M, Bergeron C, Fraser PE, St George-Hyslop P, Westaway D. 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. Abstract

Morgan D, Diamond DM, Gottschall PE, Ugen KE, Dickey C, Hardy J, Duff K, Jantzen P, DiCarlo G, Wilcock D, Connor K, Hatcher J, Hope C, Gordon M, Arendash GW. A beta peptide vaccination prevents memory loss in an animal model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):982-5. Abstract

Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, Weller RO. Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report. Nat Med. 2003 Apr;9(4):448-52. Abstract

Pfeifer M, Boncristiano S, Bondolfi L, Stalder A, Deller T, Staufenbiel M, Mathews PM, Jucker M. Cerebral hemorrhage after passive anti-Abeta immunotherapy. Science. 2002 Nov 15;298(5597):1379. Abstract

Schenk D. Opinion: Amyloid-beta immunotherapy for Alzheimer's disease: the end of the beginning. Nat Rev Neurosci. 2002 Oct;3(10):824-8. Abstract

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 Jul 8;400(6740):173-7. Abstract

View all comments by Dave Morgan

During the last 10 years, much evidence has been reported in support of the amyloid hypothesis for the progression of AD. However, the key finding of whether inhibitors of Aβ amyloidogenesis would lead to a cognitive improvement was missing. In this very interesting article, Hock et al. report for the first time preliminary results indicating that this may be the case. In addition to the practical implications for treatment, in my opinion the great importance of this study, as well as the previous publication by Nicoll et al., is that it provides crucial data to understand the molecular mechanism of AD pathogenesis in humans. It should also boost the race to develop safer immunization strategies and other anti-Aβ production, misfolding, and aggregation approaches for AD treatment. I concur with Winblad and Blum's caution on the interpretation of results with very small number of patients, but Hock, Nitsch, and colleagues should be congratulated for making these results public and imitated by the rest of the...  Read more

During the last 10 years, much evidence has been reported in support of the amyloid hypothesis for the progression of AD. However, the key finding of whether inhibitors of Aβ amyloidogenesis would lead to a cognitive improvement was missing. In this very interesting article, Hock et al. report for the first time preliminary results indicating that this may be the case. In addition to the practical implications for treatment, in my opinion the great importance of this study, as well as the previous publication by Nicoll et al., is that it provides crucial data to understand the molecular mechanism of AD pathogenesis in humans. It should also boost the race to develop safer immunization strategies and other anti-Aβ production, misfolding, and aggregation approaches for AD treatment. I concur with Winblad and Blum's caution on the interpretation of results with very small number of patients, but Hock, Nitsch, and colleagues should be congratulated for making these results public and imitated by the rest of the centers involved in the Elan Phase II trial.

View all comments by Claudio Soto

This paper shows that immunization with Aβ may slow the progression of Alzheimer’s disease, but does not restore cognitive function. These results contrast with studies of immunoneutralization of Aβ in AβPP-transgenic mice, which demonstrate reversal of memory loss and restoration of cognitive function (Kotilinek et al., 2002; Dodart et al., 2002). The most likely explanation for this discrepancy is that important differences in pathology exist between AβPP-transgenic mice and Alzheimer’s disease.

During the first year following the appearance of memory deficits in Tg(APPNL)2576 mice, neurons and synapses are largely intact (Irizarry et al., 1997). During the second year, postsynaptic markers decline, while presynaptic markers and neurons remain unchanged (G. Cole and B. Hyman, personal communication). We have proposed that soluble Aβ assemblies...  Read more

This paper shows that immunization with Aβ may slow the progression of Alzheimer’s disease, but does not restore cognitive function. These results contrast with studies of immunoneutralization of Aβ in AβPP-transgenic mice, which demonstrate reversal of memory loss and restoration of cognitive function (Kotilinek et al., 2002; Dodart et al., 2002). The most likely explanation for this discrepancy is that important differences in pathology exist between AβPP-transgenic mice and Alzheimer’s disease.

During the first year following the appearance of memory deficits in Tg(APPNL)2576 mice, neurons and synapses are largely intact (Irizarry et al., 1997). During the second year, postsynaptic markers decline, while presynaptic markers and neurons remain unchanged (G. Cole and B. Hyman, personal communication). We have proposed that soluble Aβ assemblies impair memory in Tg(APPNL)2576 mice (Ashe, 2001; Westerman, 2002), and have suggested that the rapid restoration of memory by passive immunization against Aβ indicates that Aβ assemblies disrupt memory by altering neuronal function, but not neuronal structure.

Patients with Alzheimer’s disease differ from Tg(APPNL)2576 mice because they have substantial plaque and tangle deposition as well as significant cell loss in vulnerable brain regions important for memory. The relative benefit conferred by Aβ immunization in the Hock et al. paper may reflect the inhibition of the disruptive effects of Aβ assemblies on cognitive function or the improvement of certain aspects of amyloid pathology taking place in the setting of ongoing neurodegeneration. Achieving in humans the dramatic results observed in mice is more likely to occur if interventions are administered in earlier stages of disease. Understanding how to improve cognitive function in later stages of Alzheimer’s disease will require a new generation of mouse models to study.

View all comments by Karen Hsiao Ashe

One of the critical questions in β-amyloid immunotherapy is whether depletion of the amyloid plaques is accompanied by improvement in behavioral/neurophysiological impairments and in a reduction in the nerve cell death of Alzheimer’s disease. In other words, does immunization with Aβ simply clear a neuropathological byproduct, or can it cure the disease? Anti-β-amyloid immunization of the AD mouse model showed remarkable efficacy in reducing amyloid and restoring cognitive function. The present data is the first attempt to compare cognitive test results in human AD patients—a small number so far—before and one year after vaccination. Indeed, patients with serum antibodies against β-amyloid plaques showed diminished cognitive decline and slowed disease progression, and the "dose-response" relationship between antibody levels and clinical effects constitutes evidence that amyloid proteins are indeed a primary cause of Alzheimer’s symptoms. The treated patients, suffering mild or moderate dementia, received only two injections and throughout the year...  Read more

One of the critical questions in β-amyloid immunotherapy is whether depletion of the amyloid plaques is accompanied by improvement in behavioral/neurophysiological impairments and in a reduction in the nerve cell death of Alzheimer’s disease. In other words, does immunization with Aβ simply clear a neuropathological byproduct, or can it cure the disease? Anti-β-amyloid immunization of the AD mouse model showed remarkable efficacy in reducing amyloid and restoring cognitive function. The present data is the first attempt to compare cognitive test results in human AD patients—a small number so far—before and one year after vaccination. Indeed, patients with serum antibodies against β-amyloid plaques showed diminished cognitive decline and slowed disease progression, and the "dose-response" relationship between antibody levels and clinical effects constitutes evidence that amyloid proteins are indeed a primary cause of Alzheimer’s symptoms. The treated patients, suffering mild or moderate dementia, received only two injections and throughout the year were dosed with antiinflammatory and antioxidant protection drugs. Finding the antibodies 12 months after the last administration suggests an impressive long-lasting immunization effect induced by a relatively small amount of antigen. Moreover, data suggest that a low titer of antibodies is enough to affect plaque development.

Site-directed antibodies induced by various immunological approaches are aimed at treatment of a disease that is caused by abnormal conformational changes or folding of a peptide or protein, as presented in Alzheimer’s disease and other amyloidosis disorders (Solomon, 2002). However, any effective immunization strategy must identify not only the specific nature of the antigen or the epitope, but also address the formulation and method of delivery of the antigen or antibodies as a major and critical parameter.

Unfortunately, humans may develop self-antibodies when immunized with whole or fragments of AβPP. These antibodies are capable of binding to a variety of Aβ species in the brain; thus, immunization could have beneficial effects, such as inhibition of amyloid fibril formation, while microglial overactivation may lead to neuroinflammation. The consequence of this on inflammatory pathology in AD brains needs to be considered before immunization is used as a strategy for treating AD. As recently reported, interactions of human microglia with antibody-opsonized amyloid showed increased inflammation (Lue et al., 2002).

Several strategies directed towards prevention of neuroinflammation are under investigation. Active immunization with synthetic Aβ1-42 peptide reduces β-amyloid plaques in AβPP-transgenic mice without detectable toxicity, but the extension of this approach to AD patients induced a neuroinflammatory reaction in some of the study subjects, precluding further testing of the preparation. Vaccination with nontoxic, small antiaggregating epitopes of AβPP may partially avoid the undesirable effects of neuroinflammation, e.g., by preventing T cell activation (Frenkel et al., 2003).

Administration of intravenous immunoglobulin (IVIG), which has well-recognized antiinflammatory activities independent of the antigen-specific effect, may modulate the inhibitory FcR pathway, thus controlling autoantibody-mediated inflammation induced by self-antigens or antibodies in immunotherapeutic strategies for treatment of AD. Another approach may be passive immunization with antibodies devoid of Fc, which may prevent overactivation of microglia and, thus, attenuation of autoantibody-triggered neuroinflammation. Progress in vector development for brain delivery of such antibodies, as well as clearance of immunocomplex devoid of Fc region, was recently reported (Frenkel and Solomon, 2002).

Many important questions remain open. Is the reported improvement in the behavior of AD patients caused by dissolving existing plaques or preventing formation of new plaques, or is it caused by sequestration of soluble AβPP? How many antibodies are required? How can inflammation and/or overactivation of microglia be prevented? In spite of these questions, the immunotherapeutic approach towards amyloid peptide remains the most fascinating therapeutic target for generating agents potentially able to modify the natural history of AD.

References:
Solomon B. Immunological approaches as therapy for Alzheimer's disease. Expert Opin Biol Ther. 2002 Dec;2(8):907-17. Abstract

Lue LF, Walker DG. Modeling Alzheimer's disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide. J Neurosci Res. 2002 Nov 15;70(4):599-610. Abstract

Frenkel D, Dewachter I, Van Leuven F, Solomon B. Reduction of beta-amyloid plaques in brain of transgenic mouse model of Alzheimer's disease by EFRH-phage immunization. Vaccine. 2003 Mar 7;21(11-12):1060-5. Abstract

Frenkel D, Solomon B. Filamentous phage as vector-mediated antibody delivery to the brain. Proc Natl Acad Sci U S A. 2002 Apr 16;99(8):5675-9. Abstract

View all comments by Beka Solomon

I am really happy that science is going to immunotherapy of Alzheimer's disease. I presented some of my data at the 6th International Conference on Alzheimer's Disease and Related Disorders, July 1998 in Amsterdam, The Netherlands, and this data is published. When I presented disappearing diffuse amyloid plaques in brain in my experimental model and proposed as a mechanism that they probably were disappearing because of "possible immunization," the leading scientists in the Alzheimer's disease arena did not believe me. Next I published a full paper in NeuroReport. In the discussion I write, "Probably antibodies against amyloid might act as an artificial chaperone for extra- and intracellular amyloid. Our data raise the possibility of vaccination with amyloid against AD (Alzheimer's disease)." In conclusion: "Collectively, the results raise the possibility that frequent injection with amyloid may be sufficient in preventing and treating the...  Read more

I am really happy that science is going to immunotherapy of Alzheimer's disease. I presented some of my data at the 6th International Conference on Alzheimer's Disease and Related Disorders, July 1998 in Amsterdam, The Netherlands, and this data is published. When I presented disappearing diffuse amyloid plaques in brain in my experimental model and proposed as a mechanism that they probably were disappearing because of "possible immunization," the leading scientists in the Alzheimer's disease arena did not believe me. Next I published a full paper in NeuroReport. In the discussion I write, "Probably antibodies against amyloid might act as an artificial chaperone for extra- and intracellular amyloid. Our data raise the possibility of vaccination with amyloid against AD (Alzheimer's disease)." In conclusion: "Collectively, the results raise the possibility that frequent injection with amyloid may be sufficient in preventing and treating the development of amyloid plaque formation in AD (Alzheimer's disease)."

View all comments by Ryszard Pluta

"Until the Last Dog(ma) Dies": Some Neuritic Dystrophy Is Reversible by Passive Immunization of PDAPP Mice
A multidisciplinary group has demonstrated that at least some neuritic dystrophy in PDAPP mice is reversible. Holtzman from Wash U, Paul from Lilly, Mathis and Klunk from Pitt, and Bacskai and Hyman from MGH contributed their considerable talent to a new paper in the current issue of The Journal of Clinical Investigation. Using the open skull method and Congo red derivative methoxy-X04 devised by the MGH and Pittsburgh groups, respectively, the team followed with serial imaging the morphology of swollen (dystrophic) neurites surrounding cortical amyloid deposits in the PDAPP mouse. Conventional wisdom would have predicted that these swellings might be permanent, but the new paper describes how passive immunization with anti-Aβ antibodies had a significant effect on partially normalizing the shapes of the processes.

The new paper builds on earlier work by the MGH group (Lombardo et al., 2003): The advance of...  Read more

"Until the Last Dog(ma) Dies": Some Neuritic Dystrophy Is Reversible by Passive Immunization of PDAPP Mice
A multidisciplinary group has demonstrated that at least some neuritic dystrophy in PDAPP mice is reversible. Holtzman from Wash U, Paul from Lilly, Mathis and Klunk from Pitt, and Bacskai and Hyman from MGH contributed their considerable talent to a new paper in the current issue of The Journal of Clinical Investigation. Using the open skull method and Congo red derivative methoxy-X04 devised by the MGH and Pittsburgh groups, respectively, the team followed with serial imaging the morphology of swollen (dystrophic) neurites surrounding cortical amyloid deposits in the PDAPP mouse. Conventional wisdom would have predicted that these swellings might be permanent, but the new paper describes how passive immunization with anti-Aβ antibodies had a significant effect on partially normalizing the shapes of the processes.

The new paper builds on earlier work by the MGH group (Lombardo et al., 2003): The advance of the JCI paper is to study the same plaques serially during life, while the Lombardo paper relied on postmortem analysis. A key novelty is directly demonstrating a significant trend toward normalization of existing dystrophic neurites, i.e., watching the same, flagrantly abnormal neurites partially recover their normal morphology, thereby unequivocally documenting the reversibility of neuritic dystrophy.

This dovetails well with the recent report in Neuron by Oddo and colleagues (see ARF related news story) who showed that amyloid deposits and neuritic antigens were attenuated by active immunization. Janus and colleagues (Janus et al., 2000) demonstrated Aβ-dependent behavioral deficits that were reversible with active immunization, and the Holtzman paper suggests that the same may be true for passive treatment. Together, the papers portend well for the principle that Alzheimer's pathology may be treatable, even after significant dystrophy has developed.

This is important because the most sensitive means of detecting Alzheimer's today remains neuropsychological testing, implying, by definition, the existence of pathology and deficits that one would like to reverse, if possible. Interestingly, a recent PNAS paper (Lu et al., 2005) indicates that iconic memory deficits may predict Alzheimer's even before any important deficit is present or even otherwise detectable. All the usual mice-aren't-men caveats apply, of course, but these papers are very exciting because frontiers have been pushed back both in terms of early diagnosis as well as providing optimism for reversibility of pathology.

View all comments by Samuel Gandy

Thank you for offering such a variety of papers by people who are spending their lives looking for answers.

PS: Footnotes for lay persons would help.

View all comments by Elizabeth Petersen