Sci. Aging Knowl. Environ., 7 July 2004
Vol. 2004, Issue 27, p. pe29
[DOI: 10.1126/sageke.2004.27.pe29]

PERSPECTIVES

Immunotherapy for Alzheimer's Disease

Patrick L. McGeer, and Edith McGeer

The authors are in the Kinsmen Laboratory of Neurological Research at the University of British Columbia, Vancouver, BC V6T1Z3, Canada. E-mail: mcgeerpl{at}interchange.ubc.ca (P.L.M.)

http://sageke.sciencemag.org/cgi/content/full/2004/27/pe29

Key Words: neuroinflammation • complement • vaccine • nonsteroidal anti-inflammatory drugs • innate immune system • adaptive immune system

Inflammation and Alzheimer's Disease

In terms of brain pathology, the overt hallmarks of Alzheimer's disease (AD) are generally considered to be extracellular senile plaques containing {beta}-amyloid (A{beta}) protein deposits and neurofibrillary tangles of the microtubule-associated protein tau (see "Detangling Alzheimer's Disease"). But there is a third and less widely known hallmark that cannot be overlooked: neuroinflammation. Areas affected by neuroinflammation display activated microglia (the brain's representatives of the phagocytic cells that are designed to clean up debris and foreign bacteria) surrounding the senile plaques and extracellular neurofibrillary tangles, as well as reactive astrocytes that typically wall off the affected foci (Fig. 1). Inflammation, of course, is not a specific hallmark of disease. It is a vital host defense mechanism, and in the overwhelming majority of circumstances it has a beneficial effect. Inflammation can only be considered a hallmark of disease if it clearly exacerbates the relevant pathology. This is unequivocally the case for AD. AD lesions are characterized by the presence of a series of inflammatory mediators, including cytokines, chemokines, proteases, adhesion molecules, free radicals, pentraxins, prostaglandins, anaphylatoxins, and activated complement proteins [for reviews see (1, 2) as well as McGeer Review]. Of particular importance is the association of the membrane attack complex (MAC) of complement with dystrophic neurites (3, 4). The MAC is designed to destroy foreign pathogens by inserting itself into their cell membranes, but it can also damage viable host tissue in a process known as bystander lysis. The presence of the MAC in AD provides prima facie evidence of autodestruction caused by inflammatory overactivity (for information about a possible protective role for complement and inflammation in a mouse model of AD, see "Taking Complement Well").



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Fig. 1. Inflammation in AD. An amyloid plaque (white) is surrounded by reactive astrocytes (brown). A cluster of microglial cells (black) is on top of the plaque.

 
The conclusion that inflammation exacerbates AD pathology is now supported by more than 20 epidemiological studies showing that individuals are spared AD if they have been taking anti-inflammatory drugs or have suffered from unrelated conditions for which such drugs are routinely used (5). This effect has been particularly evident in people using nonsteroidal anti-inflammatory drugs (NSAIDs, a group of drugs that inhibit cyclooxygenase, which catalyzes a step in prostaglandin synthesis), because these are the most widely used agents in various arthritic conditions. Three large epidemiological studies have analyzed the effects of NSAID consumption on AD: (i) the Baltimore longitudinal study (6) showed that the risk of developing AD was reduced by approximately 60% for individuals who had used NSAIDs for longer than 2 years as compared to those who had not used these drugs; (ii) the Cache County study showed a reduction of risk of approximately 55% associated with NSAID use (7); and (iii) the Rotterdam study, where NSAID consumption was verified through prescription records, showed an 80% reduction of risk for AD (8). These studies demonstrate that inflammation contributes to the neuronal degeneration in AD and suggest that anti-inflammatory strategies might be promising ways to treat the disorder (see "More Than a Painkiller: Ibuprofen's Hidden Talent Thwarts Alzheimer's Disease" and "Protecting the Brain While Killing Pain?").

Efforts to apply this knowledge clinically have been disappointing, however. Two pilot clinical trials using therapeutic doses of the broad spectrum NSAIDs indomethacin (9) and diclofenac (10) in patients with AD showed promise. For example, in the indomethacin study, patients receiving the drug showed mild cognitive improvement over the course of the study as compared to control patients, who exhibited cognitive decline during this period. In contrast, full-sized trials using inhibitors that are selective for only one of the two forms of cyclooxygenase (11-13) or subclinical doses of the NSAID naproxen (13) or the synthetic steroid prednisone (14) failed.

Transgenic Mouse Models of AD

For many years, a major focus of AD research has been on reducing the burden of A{beta} deposits, and an important development in this line of work was the creation of the first transgenic mouse model overexpressing human A{beta} (15). This model was soon joined by other transgenic mice that incorporate different promoters and different segments of mutated versions of the gene encoding human amyloid precursor protein (APP), such as the APP23 and Tg2576 mice (16, 17). These mice all yielded similar results, namely an accumulation of extracellular human A{beta} deposits as well as deficits in learning (18).

The Amyloid Cascade Hypothesis

These animal models provided a direct test of the amyloid cascade hypothesis of AD, which argues that it is overproduction of A{beta}--and only overproduction of A{beta}--that causes the disease (19). In this view, A{beta} is a neurotoxic molecule that induces neurofibrillary tangles and causes neuronal death. Therefore, abundant overproduction of human A{beta} in transgenic mice should produce all of the hallmarks of AD. This result has not been observed, however; in fact, none of the models have shown any signs of neurofibrillary tangle development. Only a few dystrophic neurites have been observed, along with a modest increase in certain hyperphosphorylated forms of tau (17). Some investigators have described small foci of neuronal loss in these mouse models (20, 21), whereas others have reported no loss at all (22). Modest neuroinflammation has been observed, and reactive astrocytes and reactive microglia have been detected surrounding the lesions (23). It can be concluded that inflammatory processes play a role in the observed pathology, because administration of NSAIDs results in reduced amyloid plaque deposition in mouse models (24, 25), whereas reduced complement activity in doubly transgenic mice (expressing human A{beta} together with a complement-inhibitory protein) leads to increased amyloid deposition (26). Nevertheless, the intensity of inflammation observed in these transgenic mice is considerably less than that seen in authentic AD (23). It is important to note that the MAC of complement has not been observed attacking neuronal components in these transgenic mice (23).

Treatment of AD by Vaccination with A{beta}?

A new direction in AD research using transgenic animal models came with the discovery by Schenk and co-workers that A{beta} deposits could be prevented by vaccination with A{beta} 42 (the primary, 42-residue long form found in amyloid plaques) itself (27). This finding was quickly replicated in other laboratories. In these studies, antibodies that recognize A{beta} were identified in association with A{beta} deposits in the brains of transgenic mice after vaccination, establishing that an antigen-antibody interaction was taking place (28). It was even found that direct administration of antibodies to A{beta} ("passive" immunization) that did not cross the blood/brain barrier led to an efflux of A{beta} from the brain (29). Heavy preexisting A{beta} deposits were not removed by vaccination, however, indicating that there are some limits on clearance (30).

The relative ease with which the amyloid deposits in transgenic mice could be alleviated with suitable antibodies raised hopes that comparable approaches might be successful in combating AD in humans. A clinical trial was begun using the vaccine A{beta} 42 (code-named AN1792) combined with QS21, a standard adjuvant (a substance added to a vaccine that leads to an improved immune response) (28). This vaccine was administered to 298 patients with AD, with an additional 74 control AD cases receiving placebo. However, the trial was halted when meningoencephalitis (inflammation of the brain and surrounding membranes) was identified in 18 vaccinated patients as compared with none in the placebo group (31). Titers of antibody to A{beta} 42 were not correlated with the occurrence or severity of meningoencephalitis, indicating that other factors were involved in addition to antibody concentrations. Four patients who were given vaccination therapy have died, and autopsy reports have so far appeared on two of them (32, 33). There was an extensive encephalitic reaction in both cases, with a substantial infiltration of T cells and macrophages. Removal of plaques was observed in severely affected areas of the brain, but tangles remained.

These data have led to various interpretations. The designers of the trial obviously did not anticipate adverse inflammatory reactions, but others held that an autoimmune reaction should have been anticipated (34-38). Proponents of the vaccination approach have nevertheless been encouraged by certain aspects of the results. In autopsied cases, the clearance of plaques from affected areas of the brain has been interpreted as being caused by antibody-mediated phagocytosis (32, 33). However, it is known that plaque clearance occurs in the brain after an ischemic insult (during which there is too little oxygen reaching the brain) that stimulates a microglial-macrophage response (39), so the result could, at least in part, be nonspecific.

On the clinical side, it was reported that 20 out of a subset of 30 vaccinated patients who developed serum antibodies reacting against tissue amyloid plaques were doing well with respect to cognitive performance, as compared with cases not developing such antibodies (40), but results from the total cohort will be necessary in order to judge whether there was any overall benefit from the procedure.

Despite these disappointing results from the clinical trial, experiments with transgenic mice indicate that the adaptive immune system can be engaged to help clear A{beta} deposits. But is it possible to translate this successfully into treating AD, where a different set of circumstances apply? This question cannot be answered as yet, but it is causing great attention to be paid to the characteristics of the relevant immune responses, both innate and adaptive (41, 42) (for a discussion of the innate and adaptive immune systems, see Wollscheid-Lengeling Perspective and "Immunity Challenge").

Immune System Response to A{beta} Vaccination

The strategy of vaccination against AD is based on the notion of stimulating a traditional humoral immune response, whereby cognate antibodies bind A{beta}, in either a soluble or insoluble form, leading to phagocytosis. Additionally, the complement pathway is activated when the immunoglobulin Fc chain of the antigen-antibody complex acts as a ligand for complement component C1q. This interaction initiates a complement cascade, resulting in opsonization (marking for phagocytosis by the attachment of certain complement components that act as ligands for complement receptors on phagocytes) of debris such as A{beta} deposits. The immunoglobulin Fc chain also acts as a ligand for Fc{gamma} receptors on phagocytes. Whether phagocytosis by the humoral immune response or by complement activation dominates will depend on the relative concentrations of opsonized versus nonopsonized Fc chains, and the relative numbers of Fc{gamma} receptors as compared with complement receptors on the relevant microglia.

Antigen-antibody complexes are not the only method of identifying specific targets for phagocytes, however. Human A{beta} itself is a powerful complement activator (43), and moreover, it binds the pentraxin amyloid P, another complement activator (44). Because A{beta} deposits derived from human APP expressed in transgenic mice do not immunostain for mouse amyloid P (23) and are only poorly recognized by mouse C1q (45), there is a lower level of complement recognition of A{beta} deposits in the transgenic mice than in humans with AD. This difference creates a more favorable situation for stimulating antibody-mediated A{beta} clearance while still keeping complement-mediated clearance under control in mice as compared to humans. The degree to which the complement system is activated can be critical. If kept at low to moderate levels, complement activation favors phagocytosis through opsonization. But at higher levels it is autotoxic as a result of the assembly of the MAC. As MAC activity is observed in AD, further stimulation of the complement system by vaccination could be predicted to have negative consequences for neuronal survival.

Pro-Inflammatory and Anti-Inflammatory Responses

In addition to specific factors involved in antigen-antibody reactions, there are the nonspecific inflammatory factors that need to be considered for both the adaptive and innate immune systems.

Antibody production by B cells requires T cell induction, which is why adjuvants containing T-cell-reactive epitopes are used in vaccination procedures. Can antigen-adjuvant combinations be engineered so as to stimulate antibody production while suppressing unfavorable T cell reactions? This question will require further investigation.

T cell responses can be classified as TH-1 type, which is pro-inflammatory, or TH-2 type (anti-inflammatory). TH-1-type responses develop in the presence of the cytokine interleukin 12 (IL-12), with the resulting T cells expressing the pro-inflammatory mediators interferon-{gamma} (INF-{gamma}), tumor necrosis factor-{alpha} (TNF-{alpha}), and IL-1. In contrast, TH-2 cells are induced by IL-4 and secrete such anti-inflammatory cytokines as IL-4 and IL-10. There are also TH-3-type cells, which act primarily through the secretion of transforming growth factor-{beta} and IL-10 (41).

Because neuroinflammation is clearly harmful in AD, stimulating TH-1 responses should exacerbate the pathology, whereas stimulating TH-2 or even TH-3 responses might be beneficial. An indication that the latter might be possible was suggested by the outcome of intranasal A{beta} immunization in transgenic mice. This procedure appeared to induce a TH-2-type reaction, because antibodies that specifically recognize A{beta} were produced, and the brain A{beta} burden was reduced in the presence of anti-inflammatory cytokines (46).

Macrophages of the innate immune system might also be activated to a pro-inflammatory or anti-inflammatory state (47). Classical activation, initiated by IFN-{gamma} and other factors such as lipopolysaccharide (LPS), results in a flooding of surrounding tissue with inflammatory mediators, oxidizing free radicals, proapoptotic factors, and extracellular matrix (ECM)-degrading proteases (Fig. 2). The system is designed to destroy foreign microbes but might cause considerable damage to viable host tissue.



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Fig. 2. Some factors involved in microglia/macrophage activation (47).

 
Alternative activation of macrophages is initiated by IL-4 or glucocorticoids (substances produced in response to stress). The macrophages (known as microglia in the brain) secrete leukocyte-attracting chemokines, anti-inflammatory cytokines, and some ECM components (Fig. 2). Factors secreted by alternatively activated macrophages/microglia promote cell proliferation, angiogenesis, and ECM construction, thus promoting wound repair (see Reed Perspective for a discussion of angiogenesis and the ECM). Anti-inflammatory-type activation can be distinguished by the up-regulation of CD163 (M130), a member of the scavenger receptor cysteine-rich superfamily that is exclusively expressed by monocytes and macrophages. CD163 expression is suppressed by pro-inflammatory mediators such as LPS, IFN-{gamma}, and TNF-{alpha}, whereas IL-6 and the anti-inflammatory cytokine IL-10 strongly up-regulate CD163 mRNA in monocytes and macrophages (47).

A third type of macrophage activation is initiated by ligation of Fc{gamma} receptors, coupled with a macrophage stimulatory signal through any of the Toll-like receptors or the cell surface receptors CD40 or CD44. This pathway results in the production of large amounts of IL-10. Such an activation can even occur in IFN-{gamma}-primed macrophages and results in a cutting-off of IL-12 production and an induction of IL-10 production. However, the production of other inflammatory cytokines such as TNF, IL-1, and IL-6 is unaffected (47).

Much of the work on alternate forms of macrophage activation has been done using murine cells, which are easily followed because of their abundant production of nitric oxide after classical activation. However, there are indications that similar alternative pathways occur in human macrophages/microglia.

Clearly it would be beneficial, in the context of AD, to be able to switch from the inflammatory type of activation of microglia to an anti-inflammatory activation. Whether this can be done while maintaining, or even stimulating, phagocytosis remains to be established.

Conclusion

Vaccination as a viable treatment for AD faces daunting challenges. Antibody production must be induced while pro-inflammatory T cell reactions are suppressed. Antigen-antibody clearance must be stimulated without inducing collateral tissue damage by the MAC of complement. Passive immunization with preformed antibodies might avoid these problems, but this approach will only be effective if A{beta} efflux from the brain can be continuously promoted without the antibodies themselves becoming antigenic when repeatedly administered.

Finally, there is the underlying question of whether the amyloid hypothesis of AD is correct. Will reduction in the A{beta} burden, even if it can be achieved, substantially alter the course of AD? What about neurofibrillary tangles: Can they be safely ignored? Tangles are clearly neurotoxic, as shown in the known neurodegenerative tauopathies, whereas A{beta} neurotoxicity, except for the ability of A{beta} to stimulate inflammation, is questionable. Extensive autopsy studies on patients who died in the early stages of AD show that tangles precede plaques (48, 49) and that tangle development correlates with advancing symptoms of the disease.

Future research will undoubtedly address these questions. Despite doubts about the adequacy of the amyloid cascade hypothesis, the immune approach to AD treatment has stimulated much novel research that has implications for fields far beyond AD.


July 7, 2004
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Citation: P. L. McGeer, E. McGeer, Immunotherapy for Alzheimer's Disease. Sci. Aging Knowl. Environ. 2004 (27), pe29 (2004).








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