Hock C, Konietzko U, Papassotiropoulos A, Wollmer A, Streffer J, von Rotz RC, Davey G, Moritz E, Nitsch RM.
Generation of antibodies specific for beta-amyloid by vaccination of patients with Alzheimer disease.
Nat Med. 2002 Nov;8(11):1270-5.
PubMed.
The paper by Hock et al from the Zurich group was very informative. Perhaps most interesting was the discussion regarding the one patient who had meningitis symptoms. This patient had antibody titers in CSF that equaled those in plasma, indicating a severe breakdown of the blood-brain barrier. It has been observed for some time that a subset of Alzheimer patients has blood-brain barrier breakdown. If this breakdown is found in most patients with the adverse response to the vaccine, it would permit screening out those individuals who would be at risk, and identify a subset of the population who might benefit from immunotherapy.
Importantly, the study also showed considerable variability in the antibody response across the individuals studied. Combined with the adverse events noted in 5 percent of the patient population, this would suggest passive immunization approaches—a reversible therapy with known amounts of antibody—would be the most prudent next step in testing the immunotherapy approach to AD. It might be most appropriate to only include patients with a patent blood brain barrier.
The McLaurin paper was mischaracterized in the US press (AP) as suggesting that a "safe" form of the vaccine had been tested. What was shown was that, using the standard Aβ1-42 vaccine preparation initially described by the Elan group and similar to that used in the human trials, the primary epitope recognized was the N-terminal amino acids 4-10. This replicated our own work (Dickey et al.) and that of the Elan group and Beka Solomon's group, albeit using considerably more sophisticated technology. However, these authors did not test an alternative vaccine formulation, such as was described by Sigurdsson et al (see related news story) or Nicolau et al (see related news story). While McLaurin et al. did not observe CNS inflammation in young transgenic mice vaccinated against Aβ1-42, it would be intriguing to find if the vaccine might cause CNS inflammation in aged transgenic mice, or mice with opening of the blood-brain barrier, given the Hock et al results.
References:
Dickey CA, Morgan DG, Kudchodkar S, Weiner DB, Bai Y, Cao C, Gordon MN, Ugen KE.
Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1-42 peptide.
DNA Cell Biol. 2001 Nov;20(11):723-9.
PubMed.
Ever since Elan Corporation and Wyeth-Ayerst Laboratories suspended their phase 2A clinical trials of a vaccine against Aβ42 (Check, 2002), researchers have been asking why an approach that was so successful in transgenic mice caused meningoencephalitis in some human patients (eg. Atwood et al., 2002a,b; Bishop et al., 2002; Munch & Robinson, 2002a,b; Smith et al 2002a,b,c). The Hock et al. and McLaurin et al. papers are bound to revive discussion about the immunization approach.
A potential reason why some AD patients developed an adverse reaction to the vaccine is that immunization with Aβ42 might have elicited a T-helper cell 1 (Th1)-mediated response, which in turn might have stimulated a pro-inflammatory reaction (Munch and Robinson, 2002b). McLaurin and colleagues (2002) reasoned that if an immunization regime could instead activate a Th2 response, which aids B-cells, a pro-inflammatory response could be avoided. In an earlier paper, the same team had immunized TgCRND8 mice with protofibrillar/oligomeric assemblies of Aβ42 and found that these mice showed a reduction in Ab plaque burdens and an improved performance in the Morris water maze test (Janus et al., 2000). Notably, the brains of these mice did not exhibit appreciable levels of microglial activation. Could it be that they had found a way to generate antibodies to Aβ without provoking a neuroinflammatory Th1 response? The present study suggests that they have. They demonstrate that their immunization approach produces antibodies with a high affinity for residues 4-10 of human Aβ42. The antibodies bind selectively to human Aβ42 protofibrils and can prevent fibrillogenesis of Aβ in vitro. Importantly, the Aβ42-immunized sera predominantly expressed IgG2b, which is the least effective activator of the complement system. Furthermore, no increased inflammatory response was observed in splenic T-cells from these mice, and when challenged with Aβ, their pattern of cytokine production was typical of a Th2 response.
These results hold out the exciting promise of a less inflammatory approach to the treatment of AD, but a key question remains: are transgenic mice a reliable model of AD? We have commented elsewhere (Check, 2002; Munch and Robinson, 2002a,b; Smith et al., 2002a) that antibodies against human Aβ42 merely assist in removing a redundant protein that is being overexpressed in the brains of these transgenic mice. Extracellular accumulation of this protein will impede the flow of solutes in the extracellular space and will impair brain function (Robinson and Bishop, 2002). Therefore, even if the deposits of human Aβ are inert, their clearance from the brain would be expected to improve cognition. Aβ endogenous to the mouse brain is not recognized by antibodies to human Aβ because it has a different amino acid sequence, so these animals are able to maintain a normal complement of mouse Aβ. By contrast, immunization in humans aims to deplete the brain of its endogenous Aβ. Can we really be sure that this will not produce an adverse inflammatory response, or prevent Aβ from performing its important (and hitherto unrecognized) functions (Atwood et al., 2001; 2002a,b,c; Robinson, 2002; Robinson and Bishop, 2002)?
For some time now we have been warning about the potential dangers of a vaccine approach to AD (Perry et al., 2000; Smith et al., 2000; Joseph et al., 2001). Our concerns have been based on our findings that Aβ and APP may act as antioxidants (Bush et al., 2000), and also that oxidative stress not only precedes Aβ deposition in AD, but that the appearance of Aβ plaques is associated with a decrease in oxidative stress (Nunomura et al., 2001). The present results of McLaurin and colleagues (2002) or Hock et al. (2002) do nothing to address these concerns.
Hock and colleagues (2002) provided a cohort of 30 patients for the Elan AN1792 trials. They have now tested the sera from patients immunized with Aβ42 and they report that the majority contain antibodies which bind to fibrillar plaques, diffuse Aβ deposits and vascular amyloid in sections from human brains. These antibodies do not recognize cell surface APP, or full length APP in Western blots. This important finding will help to allay fears that antibodies directed against Aβ could inadvertently impair the functions of APP, or worse still, stimulate an autoimmune response against neurons (Munch and Robinson, 2002a,b).
The study also examined whether the cerebrospinal fluid (CSF) from six patients contained appreciable titers of antibodies to Aβ. Half of the patients were found to have high CSF albumin levels, indicative of a leaky blood-brain-barrier (BBB), and all of these patients had high Aβ antibody titers in their CSF. Of the three patients with an intact BBB, only one had a detectable Aβ antibody titer. These results are interesting for several reasons. First, the proportion of patients with a leaky BBB appears to be relatively high, considering that they are mildly or moderately demented (eg. Wada, 1998). Second, the presence of detectable antibodies in the CSF (and hence the brain) appears to be associated with the presence of a leaky BBB. Third, the patient diagnosed with meningoencephalitis had, by far, the highest levels of Aβ antibodies in their CSF.
The patient sample is small, but the data are consistent with the possibility that the immunization technique increases permeability of the BBB. This might occur because cytokines that increase BBB permeability, such as TNFα (Tsao et al., 2001), are released from activated macrophages in response to intravascular and perivascular deposits of Aβ. An additional mechanism relates to our speculation that perivascular Aβ deposits may help to seal leaks in the BBB. We have predicted that clearance of these protective perivascular deposits by antibody-mediated phagocytosis of Aβ could facilitate the entry of pathogens into the brain, leading to an increased risk of meningoencephalitis and other brain infections (Atwood et al., 2002a,b; see also Bishop and Robinson, 2002). If this prediction is correct, a successful immune response to Aβ could exact a high price.
The paper by Hock and colleagues is also remarkable for what it doesn't say. Here was a golden opportunity to provide answers to whether Aβ immunization in humans reduces Aβ levels in the CSF, and whether it triggers a Th1-mediated neuroinflammatory response, yet no mention was made of the Aβ levels or cytokine levels in the CSF of these patients. We wonder at the reason for this omission, and we continue to wonder whether the AD patients with high antibody titers in their CSF did in fact exhibit a slower rate of cognitive decline then their less immune counterparts. Stephen Robinson, Monash University, Clayton, Australia; Glenda Bishop, Mark Smith, George Perry, Craig Atwood, all at Case Western Reserve University, Cleveland, Ohio.
See also:
Atwood CS, Bishop GM, Perry G. and Smith MA (2002a). Don't pick the scab: Ab as a vascular sealant that protects against hemorrhage. Commentary for the Alzheimer Research Forum live chat session: Alzheimer Immunotherapy Trial Grounded - Time to Reassess Safety and Vaccine Design?
References:
Atwood CS, Bishop GM, Perry G, Smith MA.
Amyloid-beta: a vascular sealant that protects against hemorrhage?.
J Neurosci Res. 2002 Nov 1;70(3):356.
PubMed.
Atwood CS, Robinson SR, Smith MA.
Amyloid-beta: redox-metal chelator and antioxidant.
J Alzheimers Dis. 2002 Jun;4(3):203-14.
PubMed.
Bishop GM, Robinson SR, Smith MA, Perry G, Atwood CS.
Call for Elan to publish Alzheimer's trial details.
Nature. 2002 Apr 18;416(6882):677.
PubMed.
Bishop GM, Robinson SR.
The amyloid hypothesis: let sleeping dogmas lie?.
Neurobiol Aging. 2002 Nov-Dec;23(6):1101-5.
PubMed.
Bush AI, Atwood CS, Goldstein LE, Huang X, Rogers J.
Could Abeta and AbetaPP be Antioxidants?.
J Alzheimers Dis. 2000 Jun;2(2):83-84.
PubMed.
Check E.
Nerve inflammation halts trial for Alzheimer's drug.
Nature. 2002 Jan 31;415(6871):462.
PubMed.
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.
PubMed.
Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA.
Copernicus revisited: amyloid beta in Alzheimer's disease.
Neurobiol Aging. 2001 Jan-Feb;22(1):131-46.
PubMed.
Münch G, Robinson SR.
Alzheimer's vaccine: a cure as dangerous as the disease?.
J Neural Transm. 2002 Apr;109(4):537-9.
PubMed.
Münch G, Robinson SR.
Potential neurotoxic inflammatory responses to Abeta vaccination in humans.
J Neural Transm. 2002 Jul;109(7-8):1081-7.
PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA.
Oxidative damage is the earliest event in Alzheimer disease.
J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67.
PubMed.
Perry G, Nunomura A, Raina AK, Smith MA.
Amyloid-beta junkies.
Lancet. 2000 Feb 26;355(9205):757.
PubMed.
Robinson SR, Bishop GM, Lee HG, Münch G.
Lessons from the AN 1792 Alzheimer vaccine: lest we forget.
Neurobiol Aging. 2004 May-Jun;25(5):609-15.
PubMed.
Robinson SR, Bishop GM.
Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease.
Neurobiol Aging. 2002 Nov-Dec;23(6):1051-72.
PubMed.
Smith MA, Joseph JA, Perry G.
Arson. Tracking the culprit in Alzheimer's disease.
Ann N Y Acad Sci. 2000;924:35-8.
PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G.
Predicting the failure of amyloid-beta vaccine.
Lancet. 2002 May 25;359(9320):1864-5.
PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G.
Ill-fated amyloid-beta vaccine.
J Neurosci Res. 2002 Aug 1;69(3):285.
PubMed.
Smith MA, Joseph JA, Atwood CS, Perry G.
Dangers of the amyloid-beta vaccination.
Acta Neuropathol. 2002 Jul;104(1):110.
PubMed.
Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY.
Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis.
J Med Microbiol. 2001 Sep;50(9):812-21.
PubMed.
Wada H.
Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio.
Intern Med. 1998 Jun;37(6):509-13.
PubMed.
Two recent papers on Aβ immunotherapy and Alzheimer's disease provide additional insight and both describe guarded optimism for the overall approach going forward.
The paper by McLaurin et al. describes a very careful, in-depth analysis of the antibodies generated against protofibrillar Aβ1-42 preparations. The paper shows that with this preparation, the predominant epitope targeted in the mice is Aβ 4-10. Furthermore, this purified antibody preparation is highly effective in both cellular toxicity models as well as in vivo. They also demonstrate that the predominant immunological response is Th2, which is often considered to be non-inflammatory in nature.
In the simplest interpretation, these findings suggest that antibodies against a small region of Aβ are sufficient to elicit all of the benefits seen with the Aβ1-42 immunization studies that have been previously reported (Schenk et al., 1999; Morgan et al., 2000; Janus et al., 2000). It is also important to note that immunization with a smaller fragment of Aβ peptide has already been reported to be effective (Sigurdsson et al., 2001). These findings are also consistent with previously published results showing that monoclonal antibodies against Aβ (which, by definition, are only against a single epitope as well) also work very well for efficacy in vivo (Bard et al., 2000; De Mattos et al., 2001; Kotilinek et al., 2002).
The paper by Hock, C. et al. describes the first of several reports regarding the much-publicized phase II study involving Aβ1-42 immunization that was halted after 1-3 doses due to meningo-encephalitis.
In this paper, the authors examined the specificity of the antibodies generated against the Aβ peptide as well as AβPP following several doses of AN 1792. They concluded that, first, the patients clearly did make detectable antibodies specific to Aβ peptide found in pathological structures, second, anti-Aβ antibodies were specific to amyloid deposits and did not cross-react with other brain components nor with APP and, third, antibody titer was detectable in CSF of some of the patients as well as plasma of the patients.
Collectively these findings are cautiously encouraging in the context of the immunotherapy approach. They suggest that antibodies elicited by Aβ are not likely causing side effects due to spurious cross-reactivity and also show that antibodies alone do not result in side effects. Importantly, the results parallel findings in the mice where it has been shown that antibodies to Aβ can be found in both plasma and CSF. The fact that they can be seen in humans, as well, is important.
Clearly there is much still to be learned about the mechanisms by which Aβ immunotherapy (including both active and passive administration of anti-Aβ antibodies) elicits significant pathological and cognitive performance efficacy in APP-transgenic animal models of Alzheimer's disease towards the ultimate goal of clinical utility.
There appears to be a growing consensus that while immunization with Aβ1-42 (i.e. AN 1792) has resulted in unacceptable level of adverse events, i.e. encephalitis in a subset of patients, additional research and efforts are clearly warranted. At the very least, findings such as those described by McLaurin et al. and Hock et al. suggest that second-generation strategies that optimize efficacy while improving upon the initial safety profile of holo-Aβ1-42 should be pursued for clinical development for Alzheimer's disease. Specifically, these include both immunoconjugates and monoclonal antibodies to Aβ peptide. My colleagues and I at Elan and Wyeth—as well as many other scientists around the globe—remain committed to this goal for future treatment of Alzheimer's disease.
References:
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.
PubMed.
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.
PubMed.
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.
PubMed.
Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T.
Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice.
Am J Pathol. 2001 Aug;159(2):439-47.
PubMed.
Brayden DJ, Templeton L, McClean S, Barbour R, Huang J, Nguyen M, Ahern D, Motter R, Johnson-Wood K, Vasquez N, Schenk D, Seubert P.
Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice.
Vaccine. 2001 Jul 20;19(30):4185-93.
PubMed.
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM.
Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease.
Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Epub 2001 Jul 3
PubMed.
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH.
Reversible memory loss in a mouse transgenic model of Alzheimer's disease.
J Neurosci. 2002 Aug 1;22(15):6331-5.
PubMed.
Hock et al. show that in the human trial, in which subjects with AD were actively immunized with Aβ42, a percentage of these individuals develop anti-Aβ antibodies. The antibodies generated in this immunization protocol were predominantly against the N-terminus and many of them stain amyloid plaques, indicating they see Aβ in a β-sheet
conformation. There was no evidence that the antibodies generated were against AβPP. They also did not see Aβ monomers on Western blots.
Whether the antibodies would immunoprecipitate Aβ under physiological conditions from body fluids such as CSF was not tested, so it is still possible that the antibodies could see soluble Aβ in solution. The titers of the antibodies in the plasma in some individuals were sometimes high > 1:10,000, and in patients without encephalitis with an intact BBB, the CSF titers were all 1:50 or less. This is consistent with the fact that the IgG that crosses that BBB is by passive diffusion and its amount is proportional to size of the molecule (usually The take-home message is that many humans immunized with Aβ42 in the protocol did develop antibodies to β and that the antibodies do not appear to cross-react with AβPP. The results do not yet explain the side effects seen in a subset of subjects who developed meningoencephalitis. It is certainly possible that the side effects are due to T-cells, though more studies need to be done. It is useful to know that humans can generate anti-Aβ antibodies at higher titers and this information may be helpful for future work in this area.
McLaurin et al.show that immunization of TgCRND8 mice or control mice with protofibrillar aggregates of Aβ induced formation of antibodies against Aβ. The minimal peptide that the antibodies in this paradigm were generated against was sequence 4-10. The authors nicely show that these antibodies have potent effects in vitro in blocking Aβ toxicity, preventing Aβ fiber formation, and in partially deaggregating pre-formed fibrils.
The data suggest that one mechanism by which such antibodies could work in vivo is by the effects seen in vitro. The authors suggest that the effects they observe are caused by the effects of the antibodies on Aβ protofibrils/oligomers. Whether this is the way such antibodies work in vivo may be difficult to ultimately prove. There are many different features of anti-Aβ antibodies, not only to sequences 4-10 but to other regions, which could potentially have similar effects as the antibodies studied here. One may need to study a variety of antibodies, not only ones that identify different regions but also some that have different affinities or other properties, in order to understand whether the sequence is what is absolutely critical for these effects.
Nonetheless, the data show convincingly that the antibodies generated in the mice studied have potent effects in several different assays. Whether a similar protocol as studied here in mice will be useful in humans is an interesting question. The fact that there are positive clinical effects and a lessening (not an increase) in microgliosis is promising. To know whether there will side effects in humans with this type of approach will require further testing.
We would like to add just two points—on aetiological and therapeutic rather than immunological aspects—to those of Robinson et al. Firstly, the paper by Hock et al. refers in the discussion to patients who developed "aseptic meningoencephalitis." However, Elan’s press releases refer only to "inflammation of the central nervous system." In fact, the term "aseptic meningoencephalitis" means inflammation of the brain and meninges not caused by bacteria. The most usual cause is viral. In view of Elan’s spokesman stating some months ago that no viruses (or bacteria) had been detected in the CSF of the affected patients, surely this needs clarification. Even more confusingly, Elan’s press release of January 18 stated that "…the presence of virus within the cerebrospinal fluid was reported in som(sic) of the four patients under investigation." When one of us then inquired which virus had been found in CSF, we were told by Elan that the virus was herpes simplex virus type 1 (HSV1), and that it had been detected by PCR—i.e., viral DNA had been detected, not the actual virus. In fact, any viruses entering the CSF are probably very short-lived. However, after HSV1 encephalitis, the viral DNA remains in the CSF for about two weeks (while antibodies to HSV1 persist in the CSF for years). Why, therefore, did Hock et al. refer to aseptic meningoencephalitis, and in how many cases was HSV1 DNA and/or HSV1 itself sought and detected?
HSV1 is of particular interest because we detected HSV1 DNA (in so-called latent virus form) in brain of a high proportion of elderly people by PCR (Jamieson et al., 1991, et seq.). We subsequently implicated this virus, when in brain of ApoE4 carriers, as a strong risk factor for AD (Itzhaki et al., 1997; Lin et al., 1998). This has been strengthened by our findings that ApoE determines the severity of damage caused by a different virus, hepatitis C virus in liver (Wozniak et al., 2002), that it determines whether HSV1 in the peripheral nervous system causes cold sores (Itzhaki et al., 1997; Lin et al., 1998; Corder et al. 1998), and whether pre-AIDS HIV causes dementia and peripheral neuropathy.
We suggested that HSV1 in brain can reactivate from latency and that it then causes damage that is greater in APOE-e4 carriers, leading to AD. Reactivation could occur during stress, immunosuppression, or inflammation, and in turn would cause further inflammation. Thus, relevant information about the patients in the Elan trial—both those with and those without overt brain inflammation—would be of great interest. We, therefore, urge Elan to divulge the numbers and the ApoE genotypes of patients with brain inflammation, and the numbers of those in whose CSF viral DNA or virus was found. Further, we urge them to consider using antiviral agents to treat patients who developed brain inflammation.
Secondly, as far as we know, no information has been disclosed about the rate of cognitive decline in the whole group before brain inflammation occurred. Prevention of such decline is surely the "gold standard" for treatment success. Also, have the affected patients recovered or have they declined further, and just how many were affected? Again, we urge Elan to disclose the relevant information. (See also Current Hypothesis)
References:
Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF.
Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains.
J Med Virol. 1991 Apr;33(4):224-7.
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Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA.
Herpes simplex virus type 1 in brain and risk of Alzheimer's disease.
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Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL, .
Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus.
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Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, Hall C.
HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy.
Nat Med. 1998 Oct;4(10):1182-4.
PubMed.
The McLaurin et al. paper confirmed our findings that the key sequence for dissolving as well as preventing β-amyloid aggregates is the peptide 3-6 at the N-terminal of Aβ. I presented this at the 2000 International Alzheimer's Conference in Washington and then published in (PNAS). We finished the studies in transgenic mice one year later and submitted for publication in Vaccine in Dec 2001. The manuscript was kept for 10 months, and last month was accepted for publication with very minor revisions.
The Hock et al. paper is very important and timely, as it represents the first insight into the patients who received the vaccine. I don't agree with the data that these sera did not recognize the soluble monomers or oligomers of BAP. They bind to all conformations of AAβ, but not to APP.
References:
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.
PubMed.
Comments
Michigan State University
The paper by Hock et al from the Zurich group was very informative. Perhaps most interesting was the discussion regarding the one patient who had meningitis symptoms. This patient had antibody titers in CSF that equaled those in plasma, indicating a severe breakdown of the blood-brain barrier. It has been observed for some time that a subset of Alzheimer patients has blood-brain barrier breakdown. If this breakdown is found in most patients with the adverse response to the vaccine, it would permit screening out those individuals who would be at risk, and identify a subset of the population who might benefit from immunotherapy.
Importantly, the study also showed considerable variability in the antibody response across the individuals studied. Combined with the adverse events noted in 5 percent of the patient population, this would suggest passive immunization approaches—a reversible therapy with known amounts of antibody—would be the most prudent next step in testing the immunotherapy approach to AD. It might be most appropriate to only include patients with a patent blood brain barrier.
The McLaurin paper was mischaracterized in the US press (AP) as suggesting that a "safe" form of the vaccine had been tested. What was shown was that, using the standard Aβ1-42 vaccine preparation initially described by the Elan group and similar to that used in the human trials, the primary epitope recognized was the N-terminal amino acids 4-10. This replicated our own work (Dickey et al.) and that of the Elan group and Beka Solomon's group, albeit using considerably more sophisticated technology. However, these authors did not test an alternative vaccine formulation, such as was described by Sigurdsson et al (see related news story) or Nicolau et al (see related news story). While McLaurin et al. did not observe CNS inflammation in young transgenic mice vaccinated against Aβ1-42, it would be intriguing to find if the vaccine might cause CNS inflammation in aged transgenic mice, or mice with opening of the blood-brain barrier, given the Hock et al results.
References:
Dickey CA, Morgan DG, Kudchodkar S, Weiner DB, Bai Y, Cao C, Gordon MN, Ugen KE. Duration and specificity of humoral immune responses in mice vaccinated with the Alzheimer's disease-associated beta-amyloid 1-42 peptide. DNA Cell Biol. 2001 Nov;20(11):723-9. PubMed.
View all comments by Dave MorganUniversity of Wisconsin
Ever since Elan Corporation and Wyeth-Ayerst Laboratories suspended their phase 2A clinical trials of a vaccine against Aβ42 (Check, 2002), researchers have been asking why an approach that was so successful in transgenic mice caused meningoencephalitis in some human patients (eg. Atwood et al., 2002a,b; Bishop et al., 2002; Munch & Robinson, 2002a,b; Smith et al 2002a,b,c). The Hock et al. and McLaurin et al. papers are bound to revive discussion about the immunization approach.
A potential reason why some AD patients developed an adverse reaction to the vaccine is that immunization with Aβ42 might have elicited a T-helper cell 1 (Th1)-mediated response, which in turn might have stimulated a pro-inflammatory reaction (Munch and Robinson, 2002b). McLaurin and colleagues (2002) reasoned that if an immunization regime could instead activate a Th2 response, which aids B-cells, a pro-inflammatory response could be avoided. In an earlier paper, the same team had immunized TgCRND8 mice with protofibrillar/oligomeric assemblies of Aβ42 and found that these mice showed a reduction in Ab plaque burdens and an improved performance in the Morris water maze test (Janus et al., 2000). Notably, the brains of these mice did not exhibit appreciable levels of microglial activation. Could it be that they had found a way to generate antibodies to Aβ without provoking a neuroinflammatory Th1 response? The present study suggests that they have. They demonstrate that their immunization approach produces antibodies with a high affinity for residues 4-10 of human Aβ42. The antibodies bind selectively to human Aβ42 protofibrils and can prevent fibrillogenesis of Aβ in vitro. Importantly, the Aβ42-immunized sera predominantly expressed IgG2b, which is the least effective activator of the complement system. Furthermore, no increased inflammatory response was observed in splenic T-cells from these mice, and when challenged with Aβ, their pattern of cytokine production was typical of a Th2 response.
These results hold out the exciting promise of a less inflammatory approach to the treatment of AD, but a key question remains: are transgenic mice a reliable model of AD? We have commented elsewhere (Check, 2002; Munch and Robinson, 2002a,b; Smith et al., 2002a) that antibodies against human Aβ42 merely assist in removing a redundant protein that is being overexpressed in the brains of these transgenic mice. Extracellular accumulation of this protein will impede the flow of solutes in the extracellular space and will impair brain function (Robinson and Bishop, 2002). Therefore, even if the deposits of human Aβ are inert, their clearance from the brain would be expected to improve cognition. Aβ endogenous to the mouse brain is not recognized by antibodies to human Aβ because it has a different amino acid sequence, so these animals are able to maintain a normal complement of mouse Aβ. By contrast, immunization in humans aims to deplete the brain of its endogenous Aβ. Can we really be sure that this will not produce an adverse inflammatory response, or prevent Aβ from performing its important (and hitherto unrecognized) functions (Atwood et al., 2001; 2002a,b,c; Robinson, 2002; Robinson and Bishop, 2002)?
For some time now we have been warning about the potential dangers of a vaccine approach to AD (Perry et al., 2000; Smith et al., 2000; Joseph et al., 2001). Our concerns have been based on our findings that Aβ and APP may act as antioxidants (Bush et al., 2000), and also that oxidative stress not only precedes Aβ deposition in AD, but that the appearance of Aβ plaques is associated with a decrease in oxidative stress (Nunomura et al., 2001). The present results of McLaurin and colleagues (2002) or Hock et al. (2002) do nothing to address these concerns.
Hock and colleagues (2002) provided a cohort of 30 patients for the Elan AN1792 trials. They have now tested the sera from patients immunized with Aβ42 and they report that the majority contain antibodies which bind to fibrillar plaques, diffuse Aβ deposits and vascular amyloid in sections from human brains. These antibodies do not recognize cell surface APP, or full length APP in Western blots. This important finding will help to allay fears that antibodies directed against Aβ could inadvertently impair the functions of APP, or worse still, stimulate an autoimmune response against neurons (Munch and Robinson, 2002a,b).
The study also examined whether the cerebrospinal fluid (CSF) from six patients contained appreciable titers of antibodies to Aβ. Half of the patients were found to have high CSF albumin levels, indicative of a leaky blood-brain-barrier (BBB), and all of these patients had high Aβ antibody titers in their CSF. Of the three patients with an intact BBB, only one had a detectable Aβ antibody titer. These results are interesting for several reasons. First, the proportion of patients with a leaky BBB appears to be relatively high, considering that they are mildly or moderately demented (eg. Wada, 1998). Second, the presence of detectable antibodies in the CSF (and hence the brain) appears to be associated with the presence of a leaky BBB. Third, the patient diagnosed with meningoencephalitis had, by far, the highest levels of Aβ antibodies in their CSF.
The patient sample is small, but the data are consistent with the possibility that the immunization technique increases permeability of the BBB. This might occur because cytokines that increase BBB permeability, such as TNFα (Tsao et al., 2001), are released from activated macrophages in response to intravascular and perivascular deposits of Aβ. An additional mechanism relates to our speculation that perivascular Aβ deposits may help to seal leaks in the BBB. We have predicted that clearance of these protective perivascular deposits by antibody-mediated phagocytosis of Aβ could facilitate the entry of pathogens into the brain, leading to an increased risk of meningoencephalitis and other brain infections (Atwood et al., 2002a,b; see also Bishop and Robinson, 2002). If this prediction is correct, a successful immune response to Aβ could exact a high price.
The paper by Hock and colleagues is also remarkable for what it doesn't say. Here was a golden opportunity to provide answers to whether Aβ immunization in humans reduces Aβ levels in the CSF, and whether it triggers a Th1-mediated neuroinflammatory response, yet no mention was made of the Aβ levels or cytokine levels in the CSF of these patients. We wonder at the reason for this omission, and we continue to wonder whether the AD patients with high antibody titers in their CSF did in fact exhibit a slower rate of cognitive decline then their less immune counterparts. Stephen Robinson, Monash University, Clayton, Australia; Glenda Bishop, Mark Smith, George Perry, Craig Atwood, all at Case Western Reserve University, Cleveland, Ohio.
See also:
Atwood CS, Bishop GM, Perry G. and Smith MA (2002a). Don't pick the scab: Ab as a vascular sealant that protects against hemorrhage. Commentary for the Alzheimer Research Forum live chat session: Alzheimer Immunotherapy Trial Grounded - Time to Reassess Safety and Vaccine Design?
References:
Atwood CS, Bishop GM, Perry G, Smith MA. Amyloid-beta: a vascular sealant that protects against hemorrhage?. J Neurosci Res. 2002 Nov 1;70(3):356. PubMed.
Atwood CS, Robinson SR, Smith MA. Amyloid-beta: redox-metal chelator and antioxidant. J Alzheimers Dis. 2002 Jun;4(3):203-14. PubMed.
Bishop GM, Robinson SR, Smith MA, Perry G, Atwood CS. Call for Elan to publish Alzheimer's trial details. Nature. 2002 Apr 18;416(6882):677. PubMed.
Bishop GM, Robinson SR. The amyloid hypothesis: let sleeping dogmas lie?. Neurobiol Aging. 2002 Nov-Dec;23(6):1101-5. PubMed.
Bush AI, Atwood CS, Goldstein LE, Huang X, Rogers J. Could Abeta and AbetaPP be Antioxidants?. J Alzheimers Dis. 2000 Jun;2(2):83-84. PubMed.
Check E. Nerve inflammation halts trial for Alzheimer's drug. Nature. 2002 Jan 31;415(6871):462. PubMed.
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. PubMed.
Joseph J, Shukitt-Hale B, Denisova NA, Martin A, Perry G, Smith MA. Copernicus revisited: amyloid beta in Alzheimer's disease. Neurobiol Aging. 2001 Jan-Feb;22(1):131-46. PubMed.
Münch G, Robinson SR. Alzheimer's vaccine: a cure as dangerous as the disease?. J Neural Transm. 2002 Apr;109(4):537-9. PubMed.
Münch G, Robinson SR. Potential neurotoxic inflammatory responses to Abeta vaccination in humans. J Neural Transm. 2002 Jul;109(7-8):1081-7. PubMed.
Nunomura A, Perry G, Aliev G, Hirai K, Takeda A, Balraj EK, Jones PK, Ghanbari H, Wataya T, Shimohama S, Chiba S, Atwood CS, Petersen RB, Smith MA. Oxidative damage is the earliest event in Alzheimer disease. J Neuropathol Exp Neurol. 2001 Aug;60(8):759-67. PubMed.
Perry G, Nunomura A, Raina AK, Smith MA. Amyloid-beta junkies. Lancet. 2000 Feb 26;355(9205):757. PubMed.
Robinson SR, Bishop GM, Lee HG, Münch G. Lessons from the AN 1792 Alzheimer vaccine: lest we forget. Neurobiol Aging. 2004 May-Jun;25(5):609-15. PubMed.
Robinson SR, Bishop GM. Abeta as a bioflocculant: implications for the amyloid hypothesis of Alzheimer's disease. Neurobiol Aging. 2002 Nov-Dec;23(6):1051-72. PubMed.
Smith MA, Joseph JA, Perry G. Arson. Tracking the culprit in Alzheimer's disease. Ann N Y Acad Sci. 2000;924:35-8. PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G. Predicting the failure of amyloid-beta vaccine. Lancet. 2002 May 25;359(9320):1864-5. PubMed.
Smith MA, Atwood CS, Joseph JA, Perry G. Ill-fated amyloid-beta vaccine. J Neurosci Res. 2002 Aug 1;69(3):285. PubMed.
Smith MA, Joseph JA, Atwood CS, Perry G. Dangers of the amyloid-beta vaccination. Acta Neuropathol. 2002 Jul;104(1):110. PubMed.
Tsao N, Hsu HP, Wu CM, Liu CC, Lei HY. Tumour necrosis factor-alpha causes an increase in blood-brain barrier permeability during sepsis. J Med Microbiol. 2001 Sep;50(9):812-21. PubMed.
Wada H. Blood-brain barrier permeability of the demented elderly as studied by cerebrospinal fluid-serum albumin ratio. Intern Med. 1998 Jun;37(6):509-13. PubMed.
View all comments by Craig AtwoodFormer EVP, CSO, Elan Pharmaceuticals
Two recent papers on Aβ immunotherapy and Alzheimer's disease provide additional insight and both describe guarded optimism for the overall approach going forward.
The paper by McLaurin et al. describes a very careful, in-depth analysis of the antibodies generated against protofibrillar Aβ1-42 preparations. The paper shows that with this preparation, the predominant epitope targeted in the mice is Aβ 4-10. Furthermore, this purified antibody preparation is highly effective in both cellular toxicity models as well as in vivo. They also demonstrate that the predominant immunological response is Th2, which is often considered to be non-inflammatory in nature.
In the simplest interpretation, these findings suggest that antibodies against a small region of Aβ are sufficient to elicit all of the benefits seen with the Aβ1-42 immunization studies that have been previously reported (Schenk et al., 1999; Morgan et al., 2000; Janus et al., 2000). It is also important to note that immunization with a smaller fragment of Aβ peptide has already been reported to be effective (Sigurdsson et al., 2001). These findings are also consistent with previously published results showing that monoclonal antibodies against Aβ (which, by definition, are only against a single epitope as well) also work very well for efficacy in vivo (Bard et al., 2000; De Mattos et al., 2001; Kotilinek et al., 2002).
The paper by Hock, C. et al. describes the first of several reports regarding the much-publicized phase II study involving Aβ1-42 immunization that was halted after 1-3 doses due to meningo-encephalitis.
In this paper, the authors examined the specificity of the antibodies generated against the Aβ peptide as well as AβPP following several doses of AN 1792. They concluded that, first, the patients clearly did make detectable antibodies specific to Aβ peptide found in pathological structures, second, anti-Aβ antibodies were specific to amyloid deposits and did not cross-react with other brain components nor with APP and, third, antibody titer was detectable in CSF of some of the patients as well as plasma of the patients.
Collectively these findings are cautiously encouraging in the context of the immunotherapy approach. They suggest that antibodies elicited by Aβ are not likely causing side effects due to spurious cross-reactivity and also show that antibodies alone do not result in side effects. Importantly, the results parallel findings in the mice where it has been shown that antibodies to Aβ can be found in both plasma and CSF. The fact that they can be seen in humans, as well, is important.
Clearly there is much still to be learned about the mechanisms by which Aβ immunotherapy (including both active and passive administration of anti-Aβ antibodies) elicits significant pathological and cognitive performance efficacy in APP-transgenic animal models of Alzheimer's disease towards the ultimate goal of clinical utility.
There appears to be a growing consensus that while immunization with Aβ1-42 (i.e. AN 1792) has resulted in unacceptable level of adverse events, i.e. encephalitis in a subset of patients, additional research and efforts are clearly warranted. At the very least, findings such as those described by McLaurin et al. and Hock et al. suggest that second-generation strategies that optimize efficacy while improving upon the initial safety profile of holo-Aβ1-42 should be pursued for clinical development for Alzheimer's disease. Specifically, these include both immunoconjugates and monoclonal antibodies to Aβ peptide. My colleagues and I at Elan and Wyeth—as well as many other scientists around the globe—remain committed to this goal for future treatment of Alzheimer's disease.
References:
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. PubMed.
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. PubMed.
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. PubMed.
Sigurdsson EM, Scholtzova H, Mehta PD, Frangione B, Wisniewski T. Immunization with a nontoxic/nonfibrillar amyloid-beta homologous peptide reduces Alzheimer's disease-associated pathology in transgenic mice. Am J Pathol. 2001 Aug;159(2):439-47. PubMed.
Brayden DJ, Templeton L, McClean S, Barbour R, Huang J, Nguyen M, Ahern D, Motter R, Johnson-Wood K, Vasquez N, Schenk D, Seubert P. Encapsulation in biodegradable microparticles enhances serum antibody response to parenterally-delivered beta-amyloid in mice. Vaccine. 2001 Jul 20;19(30):4185-93. PubMed.
DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM, Holtzman DM. Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8850-5. Epub 2001 Jul 3 PubMed.
Kotilinek LA, Bacskai B, Westerman M, Kawarabayashi T, Younkin L, Hyman BT, Younkin S, Ashe KH. Reversible memory loss in a mouse transgenic model of Alzheimer's disease. J Neurosci. 2002 Aug 1;22(15):6331-5. PubMed.
View all comments by Dale SchenkWashington University
Hock et al. show that in the human trial, in which subjects with AD were actively immunized with Aβ42, a percentage of these individuals develop anti-Aβ antibodies. The antibodies generated in this immunization protocol were predominantly against the N-terminus and many of them stain amyloid plaques, indicating they see Aβ in a β-sheet
conformation. There was no evidence that the antibodies generated were against AβPP. They also did not see Aβ monomers on Western blots.
Whether the antibodies would immunoprecipitate Aβ under physiological conditions from body fluids such as CSF was not tested, so it is still possible that the antibodies could see soluble Aβ in solution. The titers of the antibodies in the plasma in some individuals were sometimes high > 1:10,000, and in patients without encephalitis with an intact BBB, the CSF titers were all 1:50 or less. This is consistent with the fact that the IgG that crosses that BBB is by passive diffusion and its amount is proportional to size of the molecule (usually The take-home message is that many humans immunized with Aβ42 in the protocol did develop antibodies to β and that the antibodies do not appear to cross-react with AβPP. The results do not yet explain the side effects seen in a subset of subjects who developed meningoencephalitis. It is certainly possible that the side effects are due to T-cells, though more studies need to be done. It is useful to know that humans can generate anti-Aβ antibodies at higher titers and this information may be helpful for future work in this area.
McLaurin et al.show that immunization of TgCRND8 mice or control mice with protofibrillar aggregates of Aβ induced formation of antibodies against Aβ. The minimal peptide that the antibodies in this paradigm were generated against was sequence 4-10. The authors nicely show that these antibodies have potent effects in vitro in blocking Aβ toxicity, preventing Aβ fiber formation, and in partially deaggregating pre-formed fibrils.
The data suggest that one mechanism by which such antibodies could work in vivo is by the effects seen in vitro. The authors suggest that the effects they observe are caused by the effects of the antibodies on Aβ protofibrils/oligomers. Whether this is the way such antibodies work in vivo may be difficult to ultimately prove. There are many different features of anti-Aβ antibodies, not only to sequences 4-10 but to other regions, which could potentially have similar effects as the antibodies studied here. One may need to study a variety of antibodies, not only ones that identify different regions but also some that have different affinities or other properties, in order to understand whether the sequence is what is absolutely critical for these effects.
Nonetheless, the data show convincingly that the antibodies generated in the mice studied have potent effects in several different assays. Whether a similar protocol as studied here in mice will be useful in humans is an interesting question. The fact that there are positive clinical effects and a lessening (not an increase) in microgliosis is promising. To know whether there will side effects in humans with this type of approach will require further testing.
View all comments by David HoltzmanUniversity of Manchester
We would like to add just two points—on aetiological and therapeutic rather than immunological aspects—to those of Robinson et al. Firstly, the paper by Hock et al. refers in the discussion to patients who developed "aseptic meningoencephalitis." However, Elan’s press releases refer only to "inflammation of the central nervous system." In fact, the term "aseptic meningoencephalitis" means inflammation of the brain and meninges not caused by bacteria. The most usual cause is viral. In view of Elan’s spokesman stating some months ago that no viruses (or bacteria) had been detected in the CSF of the affected patients, surely this needs clarification. Even more confusingly, Elan’s press release of January 18 stated that "…the presence of virus within the cerebrospinal fluid was reported in som(sic) of the four patients under investigation." When one of us then inquired which virus had been found in CSF, we were told by Elan that the virus was herpes simplex virus type 1 (HSV1), and that it had been detected by PCR—i.e., viral DNA had been detected, not the actual virus. In fact, any viruses entering the CSF are probably very short-lived. However, after HSV1 encephalitis, the viral DNA remains in the CSF for about two weeks (while antibodies to HSV1 persist in the CSF for years). Why, therefore, did Hock et al. refer to aseptic meningoencephalitis, and in how many cases was HSV1 DNA and/or HSV1 itself sought and detected?
HSV1 is of particular interest because we detected HSV1 DNA (in so-called latent virus form) in brain of a high proportion of elderly people by PCR (Jamieson et al., 1991, et seq.). We subsequently implicated this virus, when in brain of ApoE4 carriers, as a strong risk factor for AD (Itzhaki et al., 1997; Lin et al., 1998). This has been strengthened by our findings that ApoE determines the severity of damage caused by a different virus, hepatitis C virus in liver (Wozniak et al., 2002), that it determines whether HSV1 in the peripheral nervous system causes cold sores (Itzhaki et al., 1997; Lin et al., 1998; Corder et al. 1998), and whether pre-AIDS HIV causes dementia and peripheral neuropathy.
We suggested that HSV1 in brain can reactivate from latency and that it then causes damage that is greater in APOE-e4 carriers, leading to AD. Reactivation could occur during stress, immunosuppression, or inflammation, and in turn would cause further inflammation. Thus, relevant information about the patients in the Elan trial—both those with and those without overt brain inflammation—would be of great interest. We, therefore, urge Elan to divulge the numbers and the ApoE genotypes of patients with brain inflammation, and the numbers of those in whose CSF viral DNA or virus was found. Further, we urge them to consider using antiviral agents to treat patients who developed brain inflammation.
Secondly, as far as we know, no information has been disclosed about the rate of cognitive decline in the whole group before brain inflammation occurred. Prevention of such decline is surely the "gold standard" for treatment success. Also, have the affected patients recovered or have they declined further, and just how many were affected? Again, we urge Elan to disclose the relevant information. (See also Current Hypothesis)
References:
Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent herpes simplex virus type 1 in normal and Alzheimer's disease brains. J Med Virol. 1991 Apr;33(4):224-7. PubMed.
Itzhaki RF, Lin WR, Shang D, Wilcock GK, Faragher B, Jamieson GA. Herpes simplex virus type 1 in brain and risk of Alzheimer's disease. Lancet. 1997 Jan 25;349(9047):241-4. PubMed.
Wozniak MA, Itzhaki RF, Faragher EB, James MW, Ryder SD, Irving WL, . Apolipoprotein E-epsilon 4 protects against severe liver disease caused by hepatitis C virus. Hepatology. 2002 Aug;36(2):456-63. PubMed.
Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, Hall C. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998 Oct;4(10):1182-4. PubMed.
View all comments by Curtis DobsonTel Aviv University
The McLaurin et al. paper confirmed our findings that the key sequence for dissolving as well as preventing β-amyloid aggregates is the peptide 3-6 at the N-terminal of Aβ. I presented this at the 2000 International Alzheimer's Conference in Washington and then published in (PNAS). We finished the studies in transgenic mice one year later and submitted for publication in Vaccine in Dec 2001. The manuscript was kept for 10 months, and last month was accepted for publication with very minor revisions.
The Hock et al. paper is very important and timely, as it represents the first insight into the patients who received the vaccine. I don't agree with the data that these sera did not recognize the soluble monomers or oligomers of BAP. They bind to all conformations of AAβ, but not to APP.
References:
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. PubMed.
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