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Is there a future for vaccination as a treatment for Alzheimer’s disease?
Neurobiology of Aging 24 (2003) 391–395
Commentary
Is there a future for vaccination as a treatment for Alzheimer’s disease? Patrick L. McGeer∗ , Edith McGeer Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3 Received 5 September 2002; accepted 30 September 2002
Abstract Vaccination of APP transgenic mice with A has been shown to prevent amyloid deposits. A clinical trial of A vaccination in Alzheimer’s disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with A should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human A so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen–antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically. © 2002 Elsevier Science Inc. All rights reserved. Keywords: -Amyloid protein; Complement; Inflammation; Transgenic mice; Antibodies; Microglia
Is vaccination a viable option for treating Alzheimer’s disease (AD)? The discovery by Schenk et al. [43] that beta-amyloid protein (A) deposits in transgenic mice could be prevented by vaccination with A opened up a new field in AD research. The transgenic vaccination experiments were soon replicated in other laboratories, including demonstration of behavioral improvement [19,35]. A antibodies were identified in association with A deposits in brain, establishing that antibodies do pass the blood–brain barrier [1]. It was even found that passive administration of an A antibody that did not cross the blood–brain barrier was effective in assisting efflux of A from brain [8], although it was also found that if pre-existing deposits were heavy, vaccination was unable to reduce the load [7]. The relative ease with which the amyloid deposits in transgenic mice could be prevented by antibodies naturally raised hopes that similar strategies might work in AD. Accordingly, a clinical trial in AD using a vaccine code named AN-1742 was commenced under the sponsorship of Wyeth and Elan Pharmaceuticals. After a few months the trial was terminated due to serious inflammatory complications ∗
Corresponding author. Tel.: +1-604-822-7377; fax: +1-604-822-7086. E-mail address: [email protected] (P.L. McGeer).
developing in about 5% of patients [47,52], including one death. Should this result have been anticipated? What are the future prospects for treating AD by vaccination? Are transgenic mice a reliable model for testing vaccination paradigms for AD? Some answers to these questions may be provided by comparing the nature of the A deposits in transgenic mice with those in AD, and by considering the broader aspects of autoimmune reactions. In transgenic mice, a mutated form of the human amyloid precursor protein (APP) gene is inserted behind a promoter which enhances neuronal expression [11,16,48]. This results in high brain expression of an abnormal form of APP with consequent accumulation of human A deposits. Mutated APP seems to be a requirement since insertion of the normal human gene does not result in deposit accumulation in transgenic mice. Human A differs from mouse A in positions 5, 10 and 13 [2]. Human APP is therefore not a normal protein for mice, which may be relevant as to how transgenic mice respond to stimulation with antibodies to human A. Antibodies are generated by the immune system against epitopes perceived by the host to be foreign. They may arise in response to infection, exposure to a noxious agent, or by vaccination. They may also appear spontaneously against
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host proteins resulting in disorders collectively known as autoimmune diseases [25]. The symptoms depend on the distribution of the host protein being attacked. A single organ, or multiple organs may be involved. There are autoimmune diseases affecting the nervous system, the kidney, the gastrointestinal tract, the heart, the skin, the muscles, the reproductive organs, the joints, and the body as a whole [25]. Since production of the host protein cannot be eliminated, therapy is largely based on immunosuppression. Vaccination against any normal host protein invites an autoimmune disorder. A and its APP parent are such normal proteins. Vaccination against A may therefore produce an autoimmune reaction against APP as well as A [38]. A is only a minor product of APP since ␣-secretase is the major cleaving enzyme and the site is within the A sequence. Intact A is produced by sequential cleavage at the - and ␥-secretase sites, producing peptides 40–42 amino acids long. The mRNAs for APP, BACE (the beta-amyloid cleaving enzyme) and presenilin-1 (a component of ␥-secretase) are present in all areas of brain as well as in heart, kidney, spleen and liver [55]. A1–40 and A1–42 are constituents of CSF and plasma. There are minor shifts in the average levels of these constituents with mutations that lead to AD, and with AD itself, but these are not dramatic, and huge overlaps exist between normal and AD cases [36]. In one study, it was also found that A CSF levels were age dependent. They were highest in young individuals, lowest in those of middle age and higher in the elderly [44]. In another study, the CSF levels were reduced in AD about 30% from an average of 539 to 397 pg/ml, while tau levels were increased 350% from 181 to 638 pg/ml [30]. Why A in AD CSF should decline and tau should increase is still a matter of speculation. These data are in accord with mRNA measurements indicating that APP and A are widely produced in the body by normal individuals as well as AD cases. Although major differences in levels of production do not exist between AD cases and normals, A accumulates extracellularly in regions of brain vulnerable to AD. This may be due, in significant part, to low levels of neprilysin, the major enzyme which cleaves A [18]. Areas of the brain, such as the caudate nucleus, and peripheral organs of the body, which express high levels of neprilysin [55], never develop A deposits. The amyloid cascade hypothesis holds that A, or some form of A, is neurotoxic and that overproduction of the hypothesized neurotoxic form leads to AD [15]. Efforts to establish that A in any of its forms is neurotoxic in vivo have been, at best, controversial. It is a normal breakdown product of APP and some have suggested that it has significant physiological functions, including neuroprotection [21,40,46]. One critical test of A neurotoxicity is the effect of A deposits on neuronal survival in transgenic mice. If soluble or concentrated forms of A were neurotoxic, it would be expected to cause large neuronal losses in transgenic mice. But only limited neuronal losses have been recorded [5,49],
and some investigators have reported a total absence of neuronal loss [17]. Synaptic dystrophy does occur [5,28], as do behavioral deficits [19,35], but this is not of the same magnitude as the devastating losses in AD. One suggestion now being made is that soluble oligomers, and not monomers of A or insoluble fibrils, are responsible for neurotoxicity by interfering with synaptic function [15]. Another explanation is that the synaptic dystrophy observed in transgenic mice is due to the inflammatory responses provoked by the deposits. While efforts to prove that A or any of its forms are directly neurotoxic have been less than convincing, there is little controversy over the fact that consolidated A deposits provoke an inflammatory response, especially in AD [31,33,39]. This is manifested by the accumulation of activated microglia around senile plaques, accompanied by the presence of a spectrum of inflammatory mediators [14]. They include complement proteins and their regulators [54], inflammatory cytokines [14], acute phase reactants [33,39], proteins modified by free radical attack [41], and a host of proteases and protease inhibitors [31,39]. Supernatants from activated microglia cause death of neurons when directly applied to them in vitro [23]. The overall evidence is consistent, therefore, not with A or any of its forms being directly neurotoxic, but with consolidated A deposits activating a neuroinflammatory response. The degree of neurotoxicity should then be related to the intensity of the response. An understanding of the neuroinflammatory process, and how it might differ between transgenic mice and AD cases, may be a key to interpreting what effects might be anticipated following vaccination with A. So far, in depth analyses of the inflammatory state in APP transgenic mice have not been carried out, but activated microglia and activated astrocytes do surround the deposits [4,10,29], and treatment with the NSAID ibuprofen suppresses plaque pathology and inflammation [27]. This is consistent with inflammation being responsible for the synaptic dystrophy. Nevertheless, the inflammatory response in transgenic mice is much milder than in AD. One reason may be the chemical state of the deposits. AD senile plaques are highly insoluble, dissolving only after harsh treatment with agents such as hot formic acid. Transgenic mouse deposits are readily soluble in SDS containing buffer. AD deposits, in contrast to mouse deposits, undergo such post-translational modifications as N-terminal degradation, isomerization, racemization, pyroglutaryl formation, oxidation and cross-linking [22,24]. Presumably this accounts for their insolubility, which could also contribute to resistance to phagocytosis and an enhanced inflammatory response. Mouse deposits do not undergo extensive post-translational modifications. It would be logical to suppose that the more soluble mouse deposits would respond more readily to antibody stimulated phagocytosis. Another key factor influencing inflammation is the degree of complement activation. Human A deposited in a -sheet is a powerful activator of human complement [42]. It binds strongly to the collagen tail of human C1q [20].
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As a result, senile plaques in AD are richly decorated with activated complement fragments [39]. More ominously, dystrophic neurites within plaques demonstrate attachment of the membrane attack complex (MAC) of complement, signifying the potential for autodestruction [32,50]. Complement is a two-edged sword. It is an essential defense system of the host, but if it becomes overactivated, it can stimulate microglia to produce toxic components such as oxygen-free radicals and harmful proteases. Moreover, it can generate levels of the MAC which exceed the levels of protectin (CD59) and other host defense molecules. The chief purpose of the MAC is to insert itself into bacteria or viral pathogens, thus protecting the host from infection. But if it becomes overactive, it can insert itself into host cells causing autodestruction. In AD, complement mRNAs are elevated many fold, while protectin mRNA is not significantly increased [54]. This provides an explanation as to why the MAC is prominently associated with dystrophic neurites in AD [32,50]. A much different circumstance exists in transgenic mouse A deposits. They do not show high levels of complement activation [34], and, in our hands, the MAC of complement is not detectable. Mouse C1q poorly recognizes human A [51]. This probably explains why complement activation by amyloid deposits in transgenic mice is weak compared with AD senile plaques. Nevertheless, activated complement appears to play a role in clearing the mouse deposits since mice doubly transgenic for human APP and the soluble complement inhibiting-receptor related protein y (sCrry), which impairs complement activation, have two- to three-fold higher amyloid deposits than singly transgenic APP mice [53]. Complement activation in transgenic mice should be greatly enhanced by attachment of A antibodies to the deposits. This is because antibodies activate complement in a different fashion from A. They bind to the globular head of C1q rather than the collagen tail. Therefore, when mouse antibodies bind to human A, they will then strongly activate the mouse complement system. In turn, this will provide significant stimulation to phagocytic activity by mouse microglia due to their high levels of complement receptors. In AD, complement is already overactivated without phagocytosis being observed. Therefore, an anticipated consequence of A vaccination is further stimulation of the complement activation and further destruction of neurons and their processes. Thus, if levels of complement activation are low, and the target protein is in a state where it can be easily phagocytosed, as in transgenic mice, then antibodies can accomplish their normal function of assisting phagocytosis. But if complement activation has already reached pathological levels, and if the target is not in a state where it can be readily phagocytosed, as in AD, then antibodies will only exacerbate the pathology. Complement is not essential for antigen–antibody complexes to be phagocytosed. This can be accomplished through Fc receptors on microglia. But antibodies are almost ineffective in complement depleted serum, indicating
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that this is not a major route. The extent to which such complement independent clearance occurs in vaccinated transgenic mice is unknown. While this is also a theoretical possibility for humans, to be of benefit it would need to overwhelm the negative effect of excessive complement activation. This might be achieved with complement blockers, especially of MAC formation, but such agents have not yet been developed. In addition to the problem of excessive stimulation of complement in AD, vaccination with A introduces the risk of a more widespread autoimmune disorder. A typical autoimmune reaction against A might affect any organ, but would particularly be expected to affect high A producing regions of brain, the meninges (the source of A for Glenner’s first isolation [13]), and cerebral vasculature due to the high incidence of angiopathy in AD. Sterile meningitis, encephalitis and strokes would be expected consequences of such reactions. Alternative methods of vaccination have been proposed to circumvent the problems encountered in the canceled AD trial and to enhance therapeutic effectiveness. These include passive administration of A antibodies [8], or vaccination with modified forms of A. Such modified forms include truncated peptides [9], A fused to other ligands [37], soluble oligomers of A [26], or naked DNA coding for A sequences [6,12]. How any of these strategies could overcome the inherent problem of enhanced complement activation and autoimmune reactions is unclear. Nevertheless, it is suggested that one or more of these formulations are likely to reach clinical testing before long [15]. In summary, the prospects for effective treatment of AD by A vaccination must be weighed against the dangers of a sustained inflammatory reaction. There are no human examples of a comparable strategy being successful in autoimmune diseases. If future human vaccination experiments are to be contemplated, they should not be undertaken until full details are published regarding the complications encountered in the initial trial, including autopsy reports. At the time of this writing, which is more than 6 months following cancellation of the trial, no details have been released concerning the complications despite urgent requests that this be done [3,38]. A full and frank explanation needs to be given to any individuals who might consider participating in a future vaccination trial, that transgenic mice are only a partial model of AD, and what is beneficial in mice may be harmful in humans [45]. It is important that detailed data of past experience be made widely available so that accurate comparisons between the results of A vaccination in humans and in transgenic mice can be made and thereby act as a guide to the many researchers who are now involved in this field.
Acknowledgments Our research has been supported by grants from the Jack Brown and Family A.D. Research Fund and the Alzheimer
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Commentary
Is there a future for vaccination as a treatment for Alzheimer’s disease? Patrick L. McGeer∗ , Edith McGeer Kinsmen Laboratory of Neurological Research, Department of Psychiatry, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3 Received 5 September 2002; accepted 30 September 2002
Abstract Vaccination of APP transgenic mice with A has been shown to prevent amyloid deposits. A clinical trial of A vaccination in Alzheimer’s disease (AD) was halted due to serious neurological complications developing in some patients. Such complications were not observed in transgenic mice. Since human APP is not a mouse self-protein, vaccination of mice with A should not produce an autoimmune reaction although this would be anticipated in AD. Moreover, mouse C1q poorly recognizes human A so complement activation is much weaker in transgenic mice than in AD. Vaccination will increase complement activation through formation of antigen–antibody complexes. In mice this will enhance phagocytosis. But in AD, where complement is already overactivated, and where the senile plaques are relatively insoluble, this stimulation should increase production of the membrane attack complex, adding to the autodestruction of neurons. The future of vaccination as a therapy for AD will require surmounting the problems of autoimmune reactions generally and autotoxic complement activation specifically. © 2002 Elsevier Science Inc. All rights reserved. Keywords: -Amyloid protein; Complement; Inflammation; Transgenic mice; Antibodies; Microglia
Is vaccination a viable option for treating Alzheimer’s disease (AD)? The discovery by Schenk et al. [43] that beta-amyloid protein (A) deposits in transgenic mice could be prevented by vaccination with A opened up a new field in AD research. The transgenic vaccination experiments were soon replicated in other laboratories, including demonstration of behavioral improvement [19,35]. A antibodies were identified in association with A deposits in brain, establishing that antibodies do pass the blood–brain barrier [1]. It was even found that passive administration of an A antibody that did not cross the blood–brain barrier was effective in assisting efflux of A from brain [8], although it was also found that if pre-existing deposits were heavy, vaccination was unable to reduce the load [7]. The relative ease with which the amyloid deposits in transgenic mice could be prevented by antibodies naturally raised hopes that similar strategies might work in AD. Accordingly, a clinical trial in AD using a vaccine code named AN-1742 was commenced under the sponsorship of Wyeth and Elan Pharmaceuticals. After a few months the trial was terminated due to serious inflammatory complications ∗
Corresponding author. Tel.: +1-604-822-7377; fax: +1-604-822-7086. E-mail address: [email protected] (P.L. McGeer).
developing in about 5% of patients [47,52], including one death. Should this result have been anticipated? What are the future prospects for treating AD by vaccination? Are transgenic mice a reliable model for testing vaccination paradigms for AD? Some answers to these questions may be provided by comparing the nature of the A deposits in transgenic mice with those in AD, and by considering the broader aspects of autoimmune reactions. In transgenic mice, a mutated form of the human amyloid precursor protein (APP) gene is inserted behind a promoter which enhances neuronal expression [11,16,48]. This results in high brain expression of an abnormal form of APP with consequent accumulation of human A deposits. Mutated APP seems to be a requirement since insertion of the normal human gene does not result in deposit accumulation in transgenic mice. Human A differs from mouse A in positions 5, 10 and 13 [2]. Human APP is therefore not a normal protein for mice, which may be relevant as to how transgenic mice respond to stimulation with antibodies to human A. Antibodies are generated by the immune system against epitopes perceived by the host to be foreign. They may arise in response to infection, exposure to a noxious agent, or by vaccination. They may also appear spontaneously against
0197-4580/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 9 7 - 4 5 8 0 ( 0 2 ) 0 0 1 5 7 - 4
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host proteins resulting in disorders collectively known as autoimmune diseases [25]. The symptoms depend on the distribution of the host protein being attacked. A single organ, or multiple organs may be involved. There are autoimmune diseases affecting the nervous system, the kidney, the gastrointestinal tract, the heart, the skin, the muscles, the reproductive organs, the joints, and the body as a whole [25]. Since production of the host protein cannot be eliminated, therapy is largely based on immunosuppression. Vaccination against any normal host protein invites an autoimmune disorder. A and its APP parent are such normal proteins. Vaccination against A may therefore produce an autoimmune reaction against APP as well as A [38]. A is only a minor product of APP since ␣-secretase is the major cleaving enzyme and the site is within the A sequence. Intact A is produced by sequential cleavage at the - and ␥-secretase sites, producing peptides 40–42 amino acids long. The mRNAs for APP, BACE (the beta-amyloid cleaving enzyme) and presenilin-1 (a component of ␥-secretase) are present in all areas of brain as well as in heart, kidney, spleen and liver [55]. A1–40 and A1–42 are constituents of CSF and plasma. There are minor shifts in the average levels of these constituents with mutations that lead to AD, and with AD itself, but these are not dramatic, and huge overlaps exist between normal and AD cases [36]. In one study, it was also found that A CSF levels were age dependent. They were highest in young individuals, lowest in those of middle age and higher in the elderly [44]. In another study, the CSF levels were reduced in AD about 30% from an average of 539 to 397 pg/ml, while tau levels were increased 350% from 181 to 638 pg/ml [30]. Why A in AD CSF should decline and tau should increase is still a matter of speculation. These data are in accord with mRNA measurements indicating that APP and A are widely produced in the body by normal individuals as well as AD cases. Although major differences in levels of production do not exist between AD cases and normals, A accumulates extracellularly in regions of brain vulnerable to AD. This may be due, in significant part, to low levels of neprilysin, the major enzyme which cleaves A [18]. Areas of the brain, such as the caudate nucleus, and peripheral organs of the body, which express high levels of neprilysin [55], never develop A deposits. The amyloid cascade hypothesis holds that A, or some form of A, is neurotoxic and that overproduction of the hypothesized neurotoxic form leads to AD [15]. Efforts to establish that A in any of its forms is neurotoxic in vivo have been, at best, controversial. It is a normal breakdown product of APP and some have suggested that it has significant physiological functions, including neuroprotection [21,40,46]. One critical test of A neurotoxicity is the effect of A deposits on neuronal survival in transgenic mice. If soluble or concentrated forms of A were neurotoxic, it would be expected to cause large neuronal losses in transgenic mice. But only limited neuronal losses have been recorded [5,49],
and some investigators have reported a total absence of neuronal loss [17]. Synaptic dystrophy does occur [5,28], as do behavioral deficits [19,35], but this is not of the same magnitude as the devastating losses in AD. One suggestion now being made is that soluble oligomers, and not monomers of A or insoluble fibrils, are responsible for neurotoxicity by interfering with synaptic function [15]. Another explanation is that the synaptic dystrophy observed in transgenic mice is due to the inflammatory responses provoked by the deposits. While efforts to prove that A or any of its forms are directly neurotoxic have been less than convincing, there is little controversy over the fact that consolidated A deposits provoke an inflammatory response, especially in AD [31,33,39]. This is manifested by the accumulation of activated microglia around senile plaques, accompanied by the presence of a spectrum of inflammatory mediators [14]. They include complement proteins and their regulators [54], inflammatory cytokines [14], acute phase reactants [33,39], proteins modified by free radical attack [41], and a host of proteases and protease inhibitors [31,39]. Supernatants from activated microglia cause death of neurons when directly applied to them in vitro [23]. The overall evidence is consistent, therefore, not with A or any of its forms being directly neurotoxic, but with consolidated A deposits activating a neuroinflammatory response. The degree of neurotoxicity should then be related to the intensity of the response. An understanding of the neuroinflammatory process, and how it might differ between transgenic mice and AD cases, may be a key to interpreting what effects might be anticipated following vaccination with A. So far, in depth analyses of the inflammatory state in APP transgenic mice have not been carried out, but activated microglia and activated astrocytes do surround the deposits [4,10,29], and treatment with the NSAID ibuprofen suppresses plaque pathology and inflammation [27]. This is consistent with inflammation being responsible for the synaptic dystrophy. Nevertheless, the inflammatory response in transgenic mice is much milder than in AD. One reason may be the chemical state of the deposits. AD senile plaques are highly insoluble, dissolving only after harsh treatment with agents such as hot formic acid. Transgenic mouse deposits are readily soluble in SDS containing buffer. AD deposits, in contrast to mouse deposits, undergo such post-translational modifications as N-terminal degradation, isomerization, racemization, pyroglutaryl formation, oxidation and cross-linking [22,24]. Presumably this accounts for their insolubility, which could also contribute to resistance to phagocytosis and an enhanced inflammatory response. Mouse deposits do not undergo extensive post-translational modifications. It would be logical to suppose that the more soluble mouse deposits would respond more readily to antibody stimulated phagocytosis. Another key factor influencing inflammation is the degree of complement activation. Human A deposited in a -sheet is a powerful activator of human complement [42]. It binds strongly to the collagen tail of human C1q [20].
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As a result, senile plaques in AD are richly decorated with activated complement fragments [39]. More ominously, dystrophic neurites within plaques demonstrate attachment of the membrane attack complex (MAC) of complement, signifying the potential for autodestruction [32,50]. Complement is a two-edged sword. It is an essential defense system of the host, but if it becomes overactivated, it can stimulate microglia to produce toxic components such as oxygen-free radicals and harmful proteases. Moreover, it can generate levels of the MAC which exceed the levels of protectin (CD59) and other host defense molecules. The chief purpose of the MAC is to insert itself into bacteria or viral pathogens, thus protecting the host from infection. But if it becomes overactive, it can insert itself into host cells causing autodestruction. In AD, complement mRNAs are elevated many fold, while protectin mRNA is not significantly increased [54]. This provides an explanation as to why the MAC is prominently associated with dystrophic neurites in AD [32,50]. A much different circumstance exists in transgenic mouse A deposits. They do not show high levels of complement activation [34], and, in our hands, the MAC of complement is not detectable. Mouse C1q poorly recognizes human A [51]. This probably explains why complement activation by amyloid deposits in transgenic mice is weak compared with AD senile plaques. Nevertheless, activated complement appears to play a role in clearing the mouse deposits since mice doubly transgenic for human APP and the soluble complement inhibiting-receptor related protein y (sCrry), which impairs complement activation, have two- to three-fold higher amyloid deposits than singly transgenic APP mice [53]. Complement activation in transgenic mice should be greatly enhanced by attachment of A antibodies to the deposits. This is because antibodies activate complement in a different fashion from A. They bind to the globular head of C1q rather than the collagen tail. Therefore, when mouse antibodies bind to human A, they will then strongly activate the mouse complement system. In turn, this will provide significant stimulation to phagocytic activity by mouse microglia due to their high levels of complement receptors. In AD, complement is already overactivated without phagocytosis being observed. Therefore, an anticipated consequence of A vaccination is further stimulation of the complement activation and further destruction of neurons and their processes. Thus, if levels of complement activation are low, and the target protein is in a state where it can be easily phagocytosed, as in transgenic mice, then antibodies can accomplish their normal function of assisting phagocytosis. But if complement activation has already reached pathological levels, and if the target is not in a state where it can be readily phagocytosed, as in AD, then antibodies will only exacerbate the pathology. Complement is not essential for antigen–antibody complexes to be phagocytosed. This can be accomplished through Fc receptors on microglia. But antibodies are almost ineffective in complement depleted serum, indicating
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that this is not a major route. The extent to which such complement independent clearance occurs in vaccinated transgenic mice is unknown. While this is also a theoretical possibility for humans, to be of benefit it would need to overwhelm the negative effect of excessive complement activation. This might be achieved with complement blockers, especially of MAC formation, but such agents have not yet been developed. In addition to the problem of excessive stimulation of complement in AD, vaccination with A introduces the risk of a more widespread autoimmune disorder. A typical autoimmune reaction against A might affect any organ, but would particularly be expected to affect high A producing regions of brain, the meninges (the source of A for Glenner’s first isolation [13]), and cerebral vasculature due to the high incidence of angiopathy in AD. Sterile meningitis, encephalitis and strokes would be expected consequences of such reactions. Alternative methods of vaccination have been proposed to circumvent the problems encountered in the canceled AD trial and to enhance therapeutic effectiveness. These include passive administration of A antibodies [8], or vaccination with modified forms of A. Such modified forms include truncated peptides [9], A fused to other ligands [37], soluble oligomers of A [26], or naked DNA coding for A sequences [6,12]. How any of these strategies could overcome the inherent problem of enhanced complement activation and autoimmune reactions is unclear. Nevertheless, it is suggested that one or more of these formulations are likely to reach clinical testing before long [15]. In summary, the prospects for effective treatment of AD by A vaccination must be weighed against the dangers of a sustained inflammatory reaction. There are no human examples of a comparable strategy being successful in autoimmune diseases. If future human vaccination experiments are to be contemplated, they should not be undertaken until full details are published regarding the complications encountered in the initial trial, including autopsy reports. At the time of this writing, which is more than 6 months following cancellation of the trial, no details have been released concerning the complications despite urgent requests that this be done [3,38]. A full and frank explanation needs to be given to any individuals who might consider participating in a future vaccination trial, that transgenic mice are only a partial model of AD, and what is beneficial in mice may be harmful in humans [45]. It is important that detailed data of past experience be made widely available so that accurate comparisons between the results of A vaccination in humans and in transgenic mice can be made and thereby act as a guide to the many researchers who are now involved in this field.
Acknowledgments Our research has been supported by grants from the Jack Brown and Family A.D. Research Fund and the Alzheimer
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