Microglial chemotaxis, activation, and phagocytosis of amyloid β-peptide as linked phenomena in Alzheimer's disease

Neurochemistry International 39 (2001) 333– 340 www.elsevier.com/locate/neuint

Microglial chemotaxis, activation, and phagocytosis of amyloid b-peptide as linked phenomena in Alzheimer’s disease Joseph Rogers *, Lih-Fen Lue L.J. Roberts Center for Alzheimer’s Research, Sun Health Research Institute, P.O. Box 1278, 10515 West Santa Fe Dri6e, Sun City, AZ 85372, USA

Abstract Microglia are widely held to play important pathophysiologic roles in Alzheimer’s disease (AD). On exposure to amyloid b peptide (Ab) they exhibit chemotactic, phagocytic, phenotypic and secretory responses consistent with scavenger cell activity in a localized inflammatory setting. Because AD microglial chemotaxis, phagocytosis, and secretory activity have common, tightly linked soluble intermediaries (e.g., cytokines, chemokines), cell surface intermediaries (e.g., receptors, opsonins), and stimuli (e.g., highly inert Ab deposits and exposed neurofibrilly tangles), the mechanisms for microglial clearance of Ab are necessarily coupled to localized inflammatory mechanisms that can be cytotoxic to nearby tissue. This presents a critical dilemma for strategies to remove Ab by enhancing micoglial activation—a dilemma that warrants substantial further investigation. © 2001 Elsevier Science Ltd. All rights reserved. Keywords: Microglial chemotaxis; Amyloid b-peptide; Alzheimer’s disease

1. Introduction Since the discovery (Rogers et al., 1986, 1988; LuberNarod and Rogers, 1988) and widespread confirmation (McGeer et al., 1988; Haga et al., 1989; Styren et al., 1990; Perlmutter et al., 1993; Sasaki et al., 1997; Overmyer et al., 1999) that microglia in pathologically vulnerable regions of the Alzheimer’s disease (AD) brain profusely express the activation marker major histocompatibility complex class II cell surface glycoprotein (MHCII), increasing attention has focused on this cell type as a potential intermediary in at least two AD pathogenic mechanisms. The first is the localized, innate inflammatory response that accompanies AD pathologic hallmarks, and the second is the processing of amyloid b-peptide (Ab). We believe, in fact, that these two phenomena are linked, as suggested by multiple in vivo, in situ, and in vitro findings. That is, Ab deposits attract microglia and activate them to produce inflammatory mediators, some of which feed back to induce further chemotaxis and activation, and some of * Corresponding author. Tel.: + 1-623-876-5328; Fax: + 1-623876-5461. E-mail address: [email protected] (J. Rogers).

which cause localized tissue damage. Once at the site of Ab deposition, activated microglia attempt to phagocytose and clear the substance, perhaps leading to further activation. 2. Microglial chemotaxis to Ab Microglia cultured from the superior frontal gyrus gray matter or from the corpus callosum of AD and nondemented elderly (ND) patients exhibit pronounced chemotaxis to preaggregated Ab1-42 deposits dried down to the well floor. Within 3 weeks, the deposits are virtually carpeted by the cells (Fig. 1A –C). Similar findings have been reported for murine peritoneal macrophages and rat microglia (Davis et al., 1992; Maeda et al., 1997). Both Ab1-42 and Ab25-35, but not scrambled Ab1-42 effectively stimulate this behavior (Davis et al., 1992), and an independent replication of the Ab25-35 result has been reported (Nakai et al., 1998). When plated on AD postmortem cortical sections, rodent microglia have also been found to migrate to aggregated Ab deposits on the section (Ard et al., 1996). In addition, peripheral monocytes migrate across a human blood –brain barrier model when Ab is present on the other side (Fiala et al., 1998).

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There are likely to be multiple mediators of microglial chemotaxis to Ab. Opsonin-independent, cell surface candidates include the formyl peptide receptor (FPR) (Lorton et al., 2000), the macrophage scavenger receptor (MSR) (El Khoury et al., 1996), and the receptor for advanced glycation endproducts (RAGE) (Yan, 1997), all of which have Ab as a ligand and all of which are expressed by microglia (El Khoury et al., 1996; Yan, 1997; Lorton et al., 2000). Because Ab precursor protein (APP) transgenic mice that lack the MSR fail to show expected changes in Ab deposition, it has been suggested that the MSR does not play a role in microglial chemotaxis to and removal of Ab (Huang et al., 1999). However, to the extent that multiple other receptors and mechanisms are involved, the loss of one receptor type (e.g. the MSR) may be readily compensated for by the presence of others (e.g. FPR, RAGE). Thus, the MSR could still be an important factor in Ab responses by microglia. Soluble mediators secreted by Ab-activated microglia (see later) may also contribute to microglial chemotaxis. For example, macrophage colony stimulating factor (M-CSF), which is increased after the exposure of microglia (Lue et al., in press) and neurons (Yan, 1997) to Ab, induces microglial chemotaxis, proliferation, increased MSR expression, and enhanced microglial survival (Tomozawa et al., 1996; Yan, 1997). Ab-stimulated secretion of M-CSF is therefore likely to contribute to the accumulation of activated microglia in and around Ab plaques. Notably, when Ab plaque cores from AD patients are injected into rat brain, proliferation of microglia occurs (Frautschy et al., 1992), consistent with the effects of scavenger cell growth factors such as M-CSF1. Chemokines are so named because of their chemoattractant properties for inflammatory cells, and represent another set of soluble factors that may play a role in microglial migration and accumulation at sites of Ab deposition (Xia and Hyman, 1999). After exposure to

Ab, for example, microglia upregulate their production of the chemokines interleukin-8 (IL-8), macrophage inflammatory peptide-1a (MIP-1a), MIP-1b, and monocyte chemoattractant protein-1 (MCP-1) (Lue et al., in press, Meda et al., 1999; Yates et al., 2000). These enhanced secretory activities would be expected to feed back to recruit and sustain additional microglial chemotaxis to wherever the Ab was initially localized. Astrocytes located at the periphery of Ab deposits in vivo (Fig. 2A) and in vitro (Fig. 2B) may also contribute to microglial chemotaxis through transforming growth factor b(TGF-b) (Finch et al., 1993), MCP-1, RANTES (Johnstone et al., 1999), and other signaling mechanisms. In addition to the opsonin-independent mediators, opsonin-dependent mechanisms for microglial chemotaxis to Ab are likely to occur in AD. Classical complement opsonins, including C1q and C3a, are upregulated at sites of Ab deposition, and the microglia clustered at such sites bear receptors for them (reviewed in Neuroinflammation Working Group, 2000). With regard to signal transduction and transcriptional mechanisms, considerably less is known, although concurrent exposure to PKC and tyrosine kinase inhibitors reportedly reduces microglial migration to Ab25-35 (Nakai et al., 1998).

3. Microglial activation by Ab Exposure of cultured AD and ND white and gray matter microglia to Ab1-42 results in their activation along several dimensions. They increase their cell surface expression of MHCII (Fig. 3), a classic marker for the activation of scavenger cells, as well as show a dose-dependent increase in their secretion of the proinflammatory cytokines IL-1b, IL-6, and tumor necrosis factor-a (TNF-a), the chemokines IL-8, MIP-1a, and MCP-1, and the growth factor M-CSF (Lue et al.,

Fig. 1. Microglial chemotaxis to and phagocytosis of Ab. (A) Prior to seeding culture wells with microglia, Ab1-42 (US peptide) is dissolved in 12.5% acetonitrile and phosphate-buffered saline, and aggregated at a concentration of 1 mM at 37 °C for 2 h. An approximately 2 ml spot of the preaggregated Ab1-42 is then dried down on the floor of a poly-L-lysine coated 2 cm2 tissue culture well (phase contrast). (B) Microglia isolated from rapid autopsy of an AD patient are seeded into the well (immunohistochemistry with the microglial activation marker LN3, an antibody directed at MHCII). (C) Over the next 3 weeks, the cultured microglia migrate to the Ab spot, ultimately covering it (LN3 immunohistochemistry). (D) The Ab spot is progressively removed, and the microglia concomitantly become immunoreactive for Ab (Ab immunohistochemistry).

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Fig. 2. Relationship of astrocytes to aggregated Ab deposits. (A) Typical neuritic plaque in the AD cortex (thioflavine histofluorescence) surrounded by glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. (B) When plated in wells containing preaggregated synthetic Ab1-42 spots (asterisk), astrocytes isolated from rapid autopsy of an AD patient take up a similar position, surrounding the Ab spot with a dense layer of GFAP-immunoreactive processes (arrows).

in press). mRNAs for virtually all these proteins, and for C1qB, C3, C4, IL-1a, IL-1 receptor antagonist, and transforming growth factor-b, have been observed in AD microglia (Walker et al., 1995). IL-1b mRNA is also increased after Ab exposure to cultured AD microglia (Walker et al., 1995). Similar results of Ab stimulation have been reported for TNF-a, IL-6, IL-1b, IL-12, MCP-1, MIP-1a, MIP-1b, and IL-8 in peripheral monocytes (Fiala et al., 1998), complement component C3 in murine microglia (Haga et al., 1993), and inducible nitric oxide synthetase (iNOS) in rat microglia (Weldon et al., 1998). Although we have detected significantly elevated reactive nitrogen intermediate secretion across constitutive and Ab-stimulated conditions in AD compared with ND cultures of microglia (Lue et al., in press), the finding is controversial. On the one hand, rodent microglia are clearly capable of iNOS mRNA and nitric oxide (NO) expression (for example, Weldon et al., 1998; Kopec and Carroll, 2000). However, human fetal (Liu et al., 1996; Ding et al., 1997) and human adult (Zhao et al., 1998) microglia in culture do not appear to have this capability, and iNOS mRNA was not detected in AD microglia in a previous study (Walker et al., 1995). Multiple transcription factors are likely to play a role in the activation of AD microglia by Ab. Nuclear factor-kB and CCAAT/enhancer binding protein, for example, mediate the production of several major cytokines (e.g. IL-1, IL-6, TNF-a) and complement components (e.g. C3). Both these transcription factors are elevated in pathologically vulnerable regions of the AD brain (Rogers et al., in preparation; Terai et al., 1996; Kaltschmidt et al., 1997).

4. Microglial phagocytosis of Ab Having arrived at sites of Ab deposition (or having been there already), and having been activated by exposure to Ab, a wide range of studies suggest that microglia may phagocytose Ab fibrils. This is not totally unexpected: microglia clearly have phagocytic capabilities (Frautschy et al., 1992; Frackowiak et al., 1992; Shigematsu et al., 1992; Kopec and Carroll, 1998; Weldon et al., 1998) and, as an abnormally deposited, chronic, highly insoluble, cross-b-pleated protein, Ab aggregates have precisely the properties that are conducive to phagocytosis. Beginning with indirect evidence of microglial phagocytosis of Ab, microglia in the AD cortex have been demonstrated to contain intracytoplasmic Ab fibrils (Lewandowska et al., 1999), and this has also been found for microglia associated with aggregated Ab deposits in APP transgenic mice (Stalder et al., 1999). C-Terminal (but not N-terminal) Ab fragments have been detected in a subset of AD microglia and astrocytes in Ab-rich areas of AD brain (Akiyama et al., 1996). In APP transgenic mice, aggregated plaques are associated with hypertrophic microglia, but diffuse plaques are not (Stalder et al., 1999). An early ultrastructural study of microglia associated with Ab plaques in the AD brain reported that Ab fibrils appeared first in altered endoplasmic reticulum and deep infoldings of cell membranes, leading the authors to conclude that AD microglia secrete rather than phagocytose Ab (Frackowiak et al., 1992). A more recent study, however, found that, although microglia in Ab plaques contain intracytoplasmic bundles of membranebound Ab, the Ab does not co-localize with secretory organelles or hyalaplasm, suggesting phagocytosis

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rather than production of Ab (Hachimi and Foncin, 1994). Both functions are in fact probable, as the Ab precursor protein, APP, is widely reported to be expressed by microglia (for example, Banati et al., 1993; Monning et al., 1995). Direct evidence for microglial phagocytosis of Ab has come from culture (Frackowiak et al., 1992) and animal (Shigematsu et al., 1992; Frautschy et al., 1992; Weldon et al., 1998) studies. In culture, AD microglia not only migrate to aggregated Ab deposits, but ultimately remove it over a period of 2– 4 weeks (Fig. 1D). At the ultrastructural level, such Ab ends up in phagosomes, where it may persist for as much as 20 days (Frackowiak et al., 1992). Consistent with these findings, cultured rat microglia have a high capacity for removing synthetic Ab from serum-free medium, with the Ab subsequently being localized to the cell surface and to phagosome-like intracellular vesicles (Ard et al., 1996). Cell surface accumulation of Ab decreases and intracellular accumulation increases when serum is included, suggesting the action of carrier proteins in serum that complex with Ab and facilitate its endocytosis (Ard et al., 1996). When cultured on unfixed cryostat sections of AD cortex containing Ab plaques, rat (Ard et al., 1996; Bard et al., 2000) and human (Bard et al., 2000) microglia are unable to phagocytose

the Ab, but are able to do so if the sections are first incubated with anti-Ab antibodies, presumably opsonizing the Ab (Bard et al., 2000). Again, Ab is subsequently found in phagosome-like intracellular vesicles (Bard et al., 2000). In laboratory animals, fibrillar Ab injected into the rat striatum is rapidly phagocytosed by microglia. Astrocytes hinder this activity by forming a barrier around the Ab reminiscent of glial scarring. Soluble Ab is also cleared quickly by microglia (Weldon et al., 1998), as is APP induced by striatal kianic acid injections (Shigematsu et al., 1992). In one of the most complete studies to date, Ab cores isolated from the AD brain and injected into rat cortex and hippocampus stimulated increased numbers of microglia and astrocytes. The Ab was phagocytosed by microglia, some of which then migrated to blood vessels. At 1 month post-injection, Ab was detected along the vessel walls (Frautschy et al., 1992). As in culture studies, the microglia of APP-over-expressing transgenic mice appear to remove Ab deposits in vivo after active (Schenk et al., 1999) or passive (Bard et al., 2000) immunization against Ab, but do not detectably do so without Ab immunization. These findings have been recently replicated and extended to show that vaccination also pro-

Fig. 3. Progressive activation of microglia, as measured by MHCII expression, with exposure to Ab deposits. Parallel wells of microglia isolated from rapid autopsy of an AD patient were plated with preaggregated synthetic Ab1-42 spots, then immunostained for MHCII expression: (A) 4 days in culture; (B) 7 days in culture; (C) 21 days in culture. (D) Higher magnification of microglial MHC II immunoreactivity at 21 days in culture. MHCII expression not only increased with duration of exposure to Ab, but also was particularly enhanced when the microglia were in direct contact with Ab (compare the right half of the micrograph (outside the Ab spot) with the left half (within the Ab spot)). Direct exposure to Ab also often resulted in an enlarged, ameboid morphology, again consistent with heightened microglial activation.

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tects against memory deficits that develop in nonimmunized APP-over-expressing transgenic mice (Chen et al., 2000; Janus et al., 2000; Morgan et al., 2000). Microglial phagocytosis may also occur with respect to the amyloid plaques found in prion disorders. Astrocytes, for example, encircle the periphery of scrapie plaques, just as they do neuritic Ab plaques, and PrP within lysosomes can be demonstrated in PrP plaque-associated microglia and occasional astrocytes (Jeffrey et al., 1994). These similarities should not be surprising given the phagocytic capabilities of microglia and the abnormally deposited, chronic, aggregated, cross-b-pleated nature of the scrapie material. Several agents have been demonstrated to alter microglial phagocytosis of Ab. Estrogen, which increases peripheral macrophage phagocytosis, also increases Ab uptake by microglia, and this effect is inhibited by an estrogen receptor antagonist (Li et al., 2000). NOS inhibitors are also reported to potentiate murine microglial phagocytosis (Kopec and Carroll, 2000). By contrast, NO-generating compounds (Kopec and Carroll, 2000), as well as C1q and MSR ligands (Webster et al., 2000a), decrease murine microglial phagocytosis of Ab. Ab itself may even be a stimulator of microglial phagocytosis. After Ab exposure, murine microglia phagocytose microspheres, acetylated low-density lipoproteins and zymosan particles, processes that are inhibited if the Ab is first complexed to proteoglycans (Kopec and Carroll, 1998). Opsonization is another mechanism that could play a role in Ab phagocytosis, as it clearly does in APPover-expressing transgenic mice that have been actively (Schenk et al., 1999) or passively (Bard et al., 2000) immunized against Ab. Here, the opsonization mechanism is through the Fc region of the anti-Ab antibody (Bard et al., 2000). Since anti-Ab antibodies appear to cross the blood– brain barrier and to bind to Ab targets in the cortex (Bard et al., 2000), it may be worth noting that, in preliminary studies several years ago, we found that approximately 50% of AD and ND patients had low serum titers of anti-Ab antibodies (Rogers and Mueller-Hill, 1990, unpublished data; Shen and Rogers, 1999, unpublished data). It would be of interest to know if these antibodies participate in some limited fashion in opsonization of soluble or insoluble Ab in AD and ND patients. A second Ab opsonization mechanism may be through C1q, which is abundant in the AD cortex, avidly complexes with aggregated Ab, and is highly co-localized with Ab plaques (reviewed in Neuroinflammation Working Group, 2000). Microglia express C1qRp, the C1q receptor that enhances phagocytosis (Webster et al., 2000b).

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Several reports have suggested that, once internalized, Ab fibrils phagocytosed by microglia remain largely undegraded (Paresce et al., 1997; Chung et al., 1999; Morelli et al., 1999). If so, heightened states of microglial activation would be expected, a process called ‘frustrated phagocytosis’. Alternatively, Bard et al. (2000) presented indirect evidence that opsonized Ab is degraded when taken up by microglia. Whether degraded or undegraded, the fate of phagocytosed Ab warrants further study, as it could have important implications for other aspects of AD pathology. For example, congophilic angiopathy could reflect a failed attempt by microglia to clear phagocytosed Ab into the vasculature.

5. Critical linkage of microglial chemotaxis, activation, and phagocytosis As already summarized, the processes of microglial chemotaxis, activation, and phagocytosis of Ab are all inextricably linked by the same receptors and soluble intermediates, as well as by the same common stimulus, Ab (Fig. 4). This has important implications for therapies based on the augmentation of microglial targeting of Ab, particularly Ab vaccination and Fc receptor-coupled mechanisms (Schenk et al., 1999; Bard et al., 2000). On the one hand, most investigators would agree that the removal of Ab from the AD brain should be beneficial. If nothing else, for example, it would remove one of the major stimulants of AD inflammation. However, as linked processes, it is critically important to recognize that vaccination to stimulate microglia and to thereby enhance Ab phagocytosis may also enhance microglial secretion of inflammatory toxins. The Fc receptor-coupled mechanism put forward by Bard et al. (2000) to explain the success of Ab immunization, for example, almost certainly encompasses FcgRIII, the prototypical pro-inflammatory Fc receptor. Although anti-inflammatory FcgRI and FcgRII mechanisms also exist (for example, Sutterwala et al., 1998), they are designed to limit the scope and duration of toxic inflammatory factors that have already been produced. Thus, antibody-mediated approaches to drive microglial clearance of Ab may simultaneously drive limited but tangible inflammatory damage to the surrounding tissue. Nonsteroidal anti-inflammatory drugs (NSAIDs) may provide a useful means for resolving this paradox. In particular, NSAIDs may differentially affect scavenger cell secretion of inflammatory intermediates and scavenger cell phagocytosis of opsonized targets. Conventional therapeutic NSAID doses, for example, typically inhibit pro-inflammatory cytokine and NO

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Fig. 4. Proposed schema for microglial chemotaxis, activation, and phagocytosis of Ab. Left panel: Microglia proximal to Ab deposits are activated by multiple mechanisms, including Ab binding to the FPR, MSR, and RAGE, all of which have Ab as a ligand. With activation, the cells become less ramefied and more ameboid in appearance, and they exhibit enhanced MHCII cell surface immunoreactivity. Middle panel: Activation also increases microglial production of cytokines, chemokines, and other soluble inflammatory factors, many of which (e.g. MCP-1, MIP-1a, IL-8, M-CSF, C3) stimulate chemotaxis and activation of microglia distal to the Ab deposit. Right panel: Microglial activation is essential for and intrinsic to the phagocytosis of Ab. There is a price, however, because microglial activation also enhances the secretion of toxic inflammatory products (e.g. alternative and classical pathway complement proteins, pro-inflammatory cytokines, reactive oxygen species, NO) that cause localized tissue injury and may cause increased Ab production.

production in vivo and in vitro (for example, Du and Li, 1999; Henrotin et al., 1999), whereas the process of scavenger cell attack on opsonized targets is so powerful that it should be relatively unaffected by these agents at normal doses, particularly in comparison with steroid anti-inflammatories (for example, Kurihara et al., 1984; Fraser-Smith and Matthews, 1988; Paape et al., 1991). Indeed, some NSAIDs appear to facilitate phagocytosis (Paape et al., 1991). For this reason, physicians of patients with, say, upper respiratory infections typically do not hesitate to administer a NSAID. They do not worry that the drug will materially impede removal of virus; rather, they hope to control secondary inflammatory effects such as fever that are mediated by the soluble products of scavenger cell activation (e.g. cytokines). The same tenets are likely to hold in human applications of Ab vaccination therapy, although this possibility remains critically untested to date. Notably, a recent study demonstrated that NSAID administration to APP transgenic mice resulted not in increased, but in decreased numbers of Ab deposits (Lim et al., 2000).

Acknowledgements This work was supported by grants from the National Institute on Aging (AGO7367) (J.R.), the Arizona Center for Alzheimer’s Disease Research (J.R.), and the Alzheimer’s Association (J.R., L.-F.L.). References Akiyama, H., et al., 1996. Granules in glial cells of patients with Alzheimer’s disease are immunopositive for C-terminal sequences of beta-amyloid protein. Neurosci. Lett. 206 (2-3), 169 –172. Ard, M.D., et al., 1996. Scavenging of Alzheimer’s amyloid betaprotein by microglia in culture. J. Neurosci. Res. 43 (2), 190 –202. Banati, R.B., et al., 1993. Early and rapid de novo synthesis of Alzheimer beta A4-amyloid protein (APP) in activated microglia. Glia 9, 199 – 210. Bard, F., et al., 2000. Peripherally administered antibodies against amyloid b peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer’s disease. Nat. Med. 6, 916 – 919. Chen, G., et al., 2000. A learning deficit related to age and b-amyloid plaques in a mouse model of Alzheimer’s disease. Nature 408, 975 – 979.

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