Differential regulation of Aβ42-induced neuronal C1q synthesis and microglial activation
© Fan and Tenner; licensee BioMed Central Ltd. 2005
Received: 18 November 2004
Accepted: 10 January 2005
Published: 10 January 2005
Expression of C1q, an early component of the classical complement pathway, has been shown to be induced in neurons in hippocampal slices, following accumulation of exogenous Aβ42. Microglial activation was also detected by surface marker expression and cytokine production. To determine whether C1q induction was correlated with intraneuronal Aβ and/or microglial activation, D-(-)-2-amino-5-phosphonovaleric acid (APV, an NMDA receptor antagonist) and glycine-arginine-glycine-aspartic acid-serine-proline peptide (RGD, an integrin receptor antagonist), which blocks and enhances Aβ42 uptake, respectively, were assessed for their effect on neuronal C1q synthesis and microglial activation. APV inhibited, and RGD enhanced, microglial activation and neuronal C1q expression. However, addition of Aβ10–20 to slice cultures significantly reduced Aβ42 uptake and microglial activation, but did not alter the Aβ42-induced neuronal C1q expression. Furthermore, Aβ10–20 alone triggered C1q production in neurons, demonstrating that neither neuronal Aβ42 accumulation, nor microglial activation is required for neuronal C1q upregulation. These data are compatible with the hypothesis that multiple receptors are involved in Aβ injury and signaling in neurons. Some lead to neuronal C1q induction, whereas other(s) lead to intraneuronal accumulation of Aβ and/or stimulation of microglia.
Alzheimer's disease (AD) is the most common form of dementia in the elderly. Its main pathological features include extracellular amyloid beta (Aβ) deposition in plaques, neurofibrillary tangles (composed of hyperphosphorylated tau protein) in neurons, progressive loss of synapses and cortical/hippocampal neurons, and upregulation of inflammatory components including activated microglia and astrocytes and complement activation . Although the contribution of abnormal phosphorylation and assembly of tau to AD dementia remains a focus of investigation, therapies that interfere with Aβ production, enhance its degradation, or cause its clearance from the central nervous system (CNS) have been the center of many studies in search of a cure for this disease.
Microglial cells, when activated, are believed to be responsible for much of the Aβ clearance through receptor-mediated phagocytosis [2, 3]. Upon activation, microglia acquire features more characteristic of macrophages, including high phagocytic activity, increased expression of leukocyte common antigen (CD45), major histocompatibility complex (MHC) class II and costimulatory molecules B7, and secretion of proinflammatory substances . In addition, phagocytic microglia also participate in the removal of degenerating neurons and synapses as well as Aβ deposits (, and reviewed in ). Thus, while some microglial functions are beneficial, the destructive effects of the production of toxins (such as nitric oxide, superoxide) and proinflammatory cytokines by activated microglia apparently overcome the protective functions in the chronic stage of neuroinflammation [7, 8]. In vitro studies have shown both protection and toxicity contributed by microglia in response to Aβ depending on the state of activation of microglia [9, 10]. Correlative studies on AD patients and animal models of AD strongly suggest that accumulation of reactive microglia at sites of Aβ deposition contributes significantly to neuronal degeneration [3, 11], although decreased microglia have been reported to be associated with both lowered and enhanced neurodegeneration in transgenic animals [12, 13]. Aβ itself is believed to initiate the accumulation and activation of microglia. However, recent reports provide evidence for neuron-microglial interactions in regulating CNS inflammation . Nevertheless, the molecular mechanisms responsible for activation and regulation of microglia remain to be defined.
Complement proteins have been shown to be associated with Aβ plaques in AD brains, specifically those plaques containing the fibrillar form of the Aβ peptide . Complement proteins are elevated in neurodegenerative diseases like AD, Parkinson's disease, and Huntington's disease as well as more restricted degenerative diseases such macular degeneration and prion disease [11, 15–18]. Microglia, astrocytes, and neurons in the CNS can produce most of the complement proteins upon stimulation. C1q, a subcomponent of C1, can directly bind to fibrillar Aβ and activate complement pathways , contributing to CNS inflammation . In addition, C1q has been reported to be synthesized by neurons in several neurodegenerative diseases and animal injury models, generally as an early response to injury [20–23], possibly prior to the synthesis of other complement components.
Interestingly, C1q and, upon complement activation, C3 also can bind to apoptotic cells and blebs and promote ingestion of those dying cells [24–26]. Elevated levels of apoptotic markers are present in AD brain tissue suggesting that many neurons undergo apoptosis in AD [27–29]. Excess glutamate, an excitatory neurotransmitter released from injured neurons and synapses, is one of the major factors that perturb calcium homeostasis and induce apoptosis in neurons . Thus, it is reasonable to hypothesize that neuronal expression of C1q, as an early injury response, may serve a potentially beneficial role of facilitating the removal of apoptotic neurons or neuronal blebs  in diseases thereby preventing excess glutamate release, excitotoxicity, and the subsequent additional apoptosis.
We have previously reported that in rat hippocampal slice cultures treated with exogenous Aβ42, C1q expression was detected in pyramidal neurons following the internalization of Aβ peptide. This upregulation of neuronal C1q could be a response to injury from Aβ that would facilitate removal of dying cells. Concurrently, microglial activation was prominent upon Aβ treatment. In the present study, the relationship of Aβ-induced neuronal C1q production to microglia activation and Aβ uptake in slice cultures was investigated.
Materials and methods
Antibodies used in immunohistochemistry.
M. Wing, Cambridge, UK
BD/PharMingen, San Diego, CA
Chemicon, Temecula, CA
Serotec Inc, Raleigh, NC
Signet Pathology Systems, Dedham, MA
Signet Pathology Systems
PCR primers and cycling conditions for RT-PCR assay.
94°C 1 min
60°C 1 min30 sec
72°C 2 min
92°C 30 sec
58°C 1 min
72°C 1 min30 sec
94°C 30 sec
72°C 1 min
94°C 30 sec
72°C 1 min
94°C 1 min
56°C 1 min
72°C 1 min
Hippocampal slice cultures were prepared according to the method of Stoppini et al  and as described in Fan and Tenner . All experimental procedures were carried out under protocols approved by the University of California Irvine Institutional Animal Care and Use Committee. Slices prepared from hippocampi dissected from 10d-old Sprague Dawley rat pups (Charles River Laboratories, Inc., Wilmington, MA) were kept in culture for 10 to 11 days before treatment started. All reagents were added to serum-free medium (with 100 mg/L transferrin and 500 mg/L heat-treated bovine serum albumin) which was equilibrated at 37°C, 5% CO2 before addition to the slices. Aβ 1–42 or Aβ 10–20 was added to slice cultures as described previously . Briefly, peptide was added to cultures in serum-free medium at 10 or 30 μM. After 7 hours, the peptide was diluted with the addition of an equal amount of medium containing 20% heat-inactivated horse serum. Fresh peptide was applied for each day of treatment. Controls were treated the same way except without peptide. RGD or APV was added to the slice cultures at the same time as Aβ 42.
At the end of the treatment period, media was removed, the slices were washed with serum-free media and subjected to trypsinization as previously described  for 15 minutes at 4°C to remove cell surface associated, but not internalized, Aβ. After washing, slices were fixed and cut into 20 μm sections for immunohistochemistry or extracted for protein or RNA analysis as described in Fan and Tenner . Primary antibodies (anti-Aβ antibody 4G8 or 6E10; rabbit anti rat C1q antibody; CD45 (leukocyte common antigen, microglia), OX42 (CD11b/c, microglia), or ED1 (rat microglia/macrophage marker), or their corresponding control IgGs were applied at concentrations listed in Table 1, followed by biotinylated secondary antibody (Vector Labs, Burlingame, CA) and finally FITC- or Cy3-conjugated streptavidin (Jackson ImmunoResearch Laboratories, West Grove, PA). Slides were examined on an Axiovert 200 inverted microscope (Carl Zeiss Light Microscopy, Göttingen, Germany) with AxioCam (Zeiss) digital camera controlled by AxioVision program (Zeiss). Images (of the entire CA1-CA2 region of hippocampus) were analyzed with KS 300 analysis program (Zeiss) to obtain the percentage area occupied by positive immunostaining in a given field.
Slices were homogenized in ice-cold extraction buffer (10 mM triethanolamine, pH 7.4, 1 mM CaCl2, 1 mM MgCl2, 0.15 M NaCl, 0.3% NP-40) containing protease inhibitors pepstatin (2 μg/ml), leupeptin (10 μg/ml), aprotinin (10 μg/ml), and PMSF (1 mM). Protein concentration was determined by BCA assay (Pierce, Rockford, IL) using BSA provided for the standard curve.
RNA preparation and RT-PCR
Total RNA from cultures was isolated using the Trizol reagent (Life Technologies, Grand Island, NY) according to the manufacturer's instructions. RNA was treated with RNase-free DNase (Fisher, Pittsburgh, PA) to remove genomic DNA contamination. Each RNA sample was extracted from 3 to 5 hippocampal organotypic slices in the same culture insert. The reverse transcription (RT) reaction conditions were 42°C for 50 min, 70°C for 15 min. Tubes were then centrifuged briefly and held at 4°C. Primer sequences and PCR conditions are listed in Table 2. PCR products were electrophoresed in 2% agarose gel in TAE buffer and visualized with ethidium bromide luminescence. To test for differences in total RNA concentration among samples, mRNA level for rat β-actin were also determined by RT-PCR. Results were quantified using NIH image software  by measuring DNA band intensity from digital images taken on GelDoc (BIO-RAD) with Quantity One program.
NMDA receptor antagonist APV inhibits Aβ42 uptake and Aβ42-induced microglial activation and neuronal C1q production
Integrin receptor antagonist GRGDSP (RGD) peptide enhances Aβ42 uptake and Aβ42-induced microglial activation and neuronal C1q expression
It has been shown that an integrin receptor antagonist peptide, GRGDSP (RGD), can enhance Aβ ingestion by neurons in hippocampal slice cultures . Therefore, we adopted this experimental manipulation as an alternative approach to modulate the level of Aβ uptake in neurons and assess the correlation between Aβ ingestion and neuronal C1q expression. Slices were treated with no peptide, 2 mM RGD, 10 μM Aβ42, or 10 μM Aβ42 + 2 mM RGD for 3 days with fresh peptides added daily. At the end of treatments, slices were collected and processed.
Aβ10–20 blocks Aβ42 induced microglial activation but triggers C1q synthesis in hippocampal neurons
CD40, IL-8, and MCSF mRNAs are induced by Aβ42 and differentially regulated by Aβ10–20 and APV
It is known that activated microglia cells can produce pro-inflammatory cytokines, chemokines, and nitric oxide, as well as higher expression of co-stimulatory molecules like CD40 and B7 . Many of those proteins have been shown to be upregulated in microglia stimulated by Aβ in cell culture and in vivo . Semi-quantitative reverse transcriptase PCR technique was used to determine how certain inducible activation products were modified in slice cultures stimulated with exogenous Aβ42 and in the presence of Aβ10–20 or APV. Rat slices were treated with 30 μM Aβ42 +/-APV or 10 μM Aβ42 +/- 30 μM Aβ10–20 for 3 days before mRNAs were extracted from tissues. LPS, was added at 150 ng/ml for 24 hr, served as positive control, with positive detection for all molecules tested (data not shown).
RT-PCR revealed that mRNAs for CD40 and IL-8 were enhanced in Aβ treated slice cultures relative to the control after 3 days (Figure 6a and 6b). Both Aβ10–20 and APV inhibited Aβ42-triggered upregulation of CD40 (Figure 6a and 6b), consistent with the inhibition of microglial activation by both Aβ10–20 and APV assessed by immunohistochemistry. APV also blocked Aβ42-induced IL-8 expression (Figure 6b), as did Aβ10–20 (data not shown).
Macrophage-colony stimulating factor (MCSF), a proinflammatory mediator for microglial proliferation and activation, has been shown to be expressed by neurons upon Aβ stimulation . The expression of MCSF was induced in slice culture by Aβ treatment by Day 3 (Figure 6a and 6b) and this increase was blocked by the presence of APV (Figure 6b). In contrast, Aβ10–20 did not alter the Aβ42-triggered MCSF induction (Figure 6a), suggesting that MCSF may be required for microglial activation, but alone is not sufficient to induce that activation.
Previously, it has been shown that Aβ is taken up by pyramidal neurons in hippocampal slice culture and that the synthesis of complement protein C1q is induced in neurons . Here we demonstrate that blocking of Aβ42 accumulation in neurons by NMDA receptor antagonist APV and increasing Aβ42 ingestion by integrin antagonist RGD is accompanied by inhibition and elevation in neuronal C1q expression, respectively. However, Aβ10–20, which markedly inhibits Aβ42 accumulation in pyramidal neurons, does not have any inhibitory effect on neuronal C1q expression. Thus, intraneuronal accumulation of Aβ is not necessary for Aβ-mediated induction of neuronal C1q synthesis.
Since Aβ10–20 alone can induce a level of C1q expression in neurons comparable to Aβ42, it is hypothesized that amino acids 10–20 in Aβ peptide contain the sequence that is recognized by at least one Aβ receptor. It was reported by Giulian et al. that the HHQK domain (residues 13–16) in Aβ is critical for Aβ-microglia interaction and activation of microglia, as they demonstrated that small peptides containing HHQK suppress microglial activation and Aβ-induced microglial mediated neurotoxicity . We have previously reported that rat Aβ42, which differs in 3 amino acids from human Aβ42, including 2 in the 10–20 region and 1 in the HHQK domain, was internalized and accumulated in neurons but failed to induce neuronal C1q expression . This is consistent with the hypothesis that a specific Aβ interaction (either neuronal or microglial), presumably via the HHQK region of the Aβ peptide, but not intracellular Aβ accumulation, can lead to neuronal C1q induction in hippocampal neurons.
Activated glial cells, especially microglia, are major players in the neuroinflammation seen in of Alzheimer's disease . Microglial cells can be activated by Aβ and produce proinflammatory cytokines, nitric oxide, superoxide, and other potentially neurotoxic substances in vitro, although the state of differentiation/ activation of microglia and the presence of other modulating molecules is known to influence this stimulation [7, 9, 43]. "Activated" microglia also become more phagocytic and can partially ingest and degrade amyloid deposits in brain. This leads many to hypothesize that there are multiple subsets of "activated" microglia, each primed to function in a specific but distinct way [5, 43].
In hippocampal slice cultures, we and others have shown that Aβ42 triggered microglial activation as assessed by immunohistochemical detection of CR3 (OX42), and cathepsin D [34, 37]. Several chemokines, including macrophage inflammatory protein-1 (MIP-1α, MIP-1β), monocyte chemotactic protein (MCP-1), and interleukin 8 (IL-8), have been reported to increase in Alzheimer's disease patients or cell cultures treated with Aβ [44, 45]. CD40, a co-stimulatory molecule, is also upregulated in Aβ-treated microglia . In this study, similar to reports of cultured microglia, immunoreactivity of CD45 was found increased on microglia in Aβ42 treated slice cultures, and CD40 and IL-8 messenger RNAs were elevated after Aβ42 exposure. As expected, CD40 and IL-8 mRNA induction was blocked whenever immunohistochemistry analysis showed the inhibition of microglial activation. [We did not observe change in MIP-1α, 1β mRNAs in slice culture with Aβ42 treatment, and MCP-1 was too low to be detected with or without Aβ stimulation although it was detectable in LPS treated slices (data not shown).]
The data presented thus far suggest the hypothesis that neurons, upon uptake and accumulation of Aβ, release certain substances that activate microglia. One possible candidate of those neuron-produced substances is MCSF, which has been reported to be induced in neuronal cultures upon Aβ stimulation [41, 46], and is known to be able to trigger microglial activation . Indeed, MCSF mRNA was found to increase after 3 days of Aβ treatment (Figure 6a and 6b). The diminished MCSF signal with the addition of APV and coordinate lack of microglial activation is consistent with a proposed role of activating microglia by MCSF produced by stimulated neurons. However, in the presence of Aβ10–20, MCSF induction was unaltered, though microglial activation was inhibited. Thus, MCSF alone does not lead to the upregulation of the above-mentioned microglial activation markers.
In this organotypic slice culture, no significant neuronal damage was observed in 3 day treatment with Aβ at concentrations that have been reported to cause neurotoxicity in cell cultures. One possible explanation is that the peptide has to penetrate the astrocyte layer surrounding the tissue to reach the multiple layers of neurons. Thus, the effective concentration of Aβ on neurons is certainly much lower than the added concentration. Aβ failing to induce neurotoxicity in slices to the same extent as in cell cultures may also indicate the loss of certain protective mechanisms in isolated cells. A distinct advantage of the slice culture model is that the tissue contains all of the cell types present in brain, the cells are all at the same developmental stage, and cells may communicate in similar fashion as in vivo.
Our data demonstrating distinct pathways for the induction of neuronal C1q and the activation of microglial by amyloid peptides suggest the involvement of multiple Aβ receptors on multiple cell types in response to Aβ (Figure 7, model) and possibly in Alzheimer's disease progression. This multiple-receptor mechanism is supported by reports suggesting many proteins/complexes can mediate the Aβ interaction with cells . These include, but not limited to, the alpha7nicotinic acetylcholine receptor (alpha7nAChR), the P75 neurotrophin receptor (P75NTR) on neurons, the scavenger receptors and heparan sulfate proteoglycans on microglia, as well as receptor for advanced glycosylation end-products (RAGE) and integrins on both neurons and microglia (Figure 7). Several signaling pathways have been implicated in specific Aβ-receptor interactions [49–51]. However, it is not known which receptors are required for induction of C1q in neurons. In addition, as of yet the function of neuronal C1q has not been determined. Previous reports from our lab have shown that C1q is associated with hippocampal neurons in AD cases but not normal brain , and the fact that it is synthesized by the neurons has been documented by others [23, 53]. In addition, C1q was prominently expressed in a preclinical case of AD (significant diffuse amyloid deposits, with no plaque associated C1q, and no obvious cognitive disorder) and is expressed in other situations of "stress" or injury in the brain [54–58]. Indeed, overexpression of human cyclooxygenase-2 in mice leads to C1q synthesis in neurons and inhibition of COX-2 activity abrogates C1q induction. These data suggest that in addition to the facilitation of phagocytosis by microglia [59, 60] (particularly of dead cells or neuronal blebs), the induction of C1q may be an early response of neurons to injury or regulation of an inflammatory response, consistent with a role in the progression of neurodegeneration in AD. Whether and how the neuronal C1q production affects the survival of neurons is still under investigation. Identifying the receptors responsible for neuronal C1q induction may be informative in understanding the role of C1q in neurons in injury and disease.
In summary, induction of C1q expression in hippocampal neurons by exogenous Aβ42 is dependent upon specific cellular interactions with Aβ peptide that require HHQK region-containing sequence, but does not require intraneuronal accumulation of Aβ or microglial activation. Thus, induction of neuronal C1q synthesis may be an early response to injury to facilitate clearance of damaged cells, while modulating inflammation and perhaps facilitating repair. Microglial activation in slice culture involves the induction of CD45, CD40, CR3, and IL-8, which correlates with intraneuronal accumulation of Aβ, indicating contribution of factors released by neurons upon Aβ exposure. MCSF may be one of those stimulatory factors, though by itself MCSF cannot fully activate microglia.
Removal of Aβ to prevent deposition and of cellular debris to avoid excitotoxicity would be a beneficial role of microglial activation in AD. However, activated microglia also produce substances that are neurotoxic. Therefore, the goal of modulating the inflammatory response in neurodegenerative diseases like AD is to enhance the phagocytic function of glial cells and inhibit the production of proinflammatory molecules. Being able to distinguish in the slice system C1q expression (which has been shown to facilitate phagocytosis of apoptotic cells in other systems ) from microglial activation suggests a plausible approach to reach that goal in vivo.
List of abbreviations
bovine serum albumin
- GRGDSP (RGD):
Hanks' balanced salt solution
macrophage colony stimulating factor
This work is supported by NIH NS 35144 and P50 AG16573. The authors thank Dr. Saskia Milton and Dr. Charles Glabe for providing the synthetic human Aβ peptide, and Dr. Maria Fonseca, Dr. Ming Li, and Karntipa Pisalyaput for their review of this manuscript.
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