A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of β-Amyloid

β-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar β-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, β-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to β-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by β-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance. β-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar β-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, β-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to β-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by β-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance. The observation that activated microglia and astrocytes surround fibrillar β-amyloid (fAβ) 1The abbreviations used are: fAβ, fibrillar β-amyloid; MAP, mitogen-activated protein; MAPK, MAP kinase; revAβ, reverse β-amyloid peptide 42–1; ROS, reactive oxygen species; LPS, lipopolysaccharide; PTK, phosphotyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; PBS, phosphate-buffered saline; Ab, antibody(s); FITC, fluorescein isothiocyanate; DAPI, 4′,6-diamidino-2-phenylindole; MCP-1, monocyte chemoattractant protein-1 1The abbreviations used are: fAβ, fibrillar β-amyloid; MAP, mitogen-activated protein; MAPK, MAP kinase; revAβ, reverse β-amyloid peptide 42–1; ROS, reactive oxygen species; LPS, lipopolysaccharide; PTK, phosphotyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; PBS, phosphate-buffered saline; Ab, antibody(s); FITC, fluorescein isothiocyanate; DAPI, 4′,6-diamidino-2-phenylindole; MCP-1, monocyte chemoattractant protein-1 aggregates in senile plaques has led to the hypothesis that a chronic inflammatory reaction by glia may underlie the neurodegenerative events in the brains of Alzheimer's disease patients (1Akiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G.M. Cooper N.R. Eikelenboom P. Emmerling M. Fiebich B.L. Finch C.E. Frautschy S. Griffin W.S. Hampel H. Hull M. Landreth G. Lue L. Mrak R. Mackenzie I.R. McGeer P.L. O'Banion M.K. Pachter J. Pasinetti G. Plata-Salaman C. Rogers J. Rydel R. Shen Y. Streit W. Strohmeyer R. Tooyoma I. Van Muiswinkel F.L. Veerhuis R. Walker D. Webster S. Wegrzyniak B. Wenk G. Wyss-Coray T. Neurobiol. Aging. 2000; 21: 383-421Google Scholar). Central to this “inflammatory response to Aβ” hypothesis is the recruitment and activation of microglia, which, like other tissue macrophages, represent a reservoir of pro-inflammatory cytokines and chemokines capable of inciting chronic inflammation and tissue damage (2Gonzalez-Scarano F. Baltuch G. Annu. Rev. Neurosci. 1999; 22: 219-240Google Scholar). The identification of a receptor-associated signal transduction pathway that mediates the inflammatory response to β-amyloid could contribute substantially to an understanding of the etiology of Alzheimer's disease and the development of novel approaches to its treatment. We have recently reported that the class B scavenger receptor, CD36, is expressed on microglia and vascular endothelial cells in the brains of normal and Alzheimer's disease patients and can mediate binding to fibrillar β-amyloid (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). Indeed, in microglia and macrophages, β-amyloid stimulated H2O2 production could be blocked substantially by antibodies to CD36, suggesting a potential role for CD36 in mediating the inflammatory response of mononuclear phagocytes to fibrillar β-amyloid. CD36 has previously been shown to play a substantive role in the pathogenesis of atherosclerosis (4Febbraio M. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2001; 108: 785-791Google Scholar). Atherosclerosis, like Alzheimer's disease, has been postulated to result from a chronic inflammatory state (5Ross R. N. Engl. J. Med. 1999; 340: 115-126Google Scholar). CD36 is believed to play a critical role in the initiation of atherosclerotic lesions through its ability to bind and internalize modified low density lipoprotein trapped in the artery wall, facilitating the formation of lipid-engorged macrophage “foam cells” (4Febbraio M. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2001; 108: 785-791Google Scholar). Interestingly, β-amyloid was recently identified in advanced human atherosclerotic lesions, raising the possibility that non-lipid ligands of CD36 might contribute to atherogenesis through a pathway that diverges from that involved in lipid uptake (6De Meyer G.R. De Cleen D.M. Cooper S. Knaapen M.W. Jans D.M. Martinet W. Herman A.G. Bult H. Kockx M.M. Circ. Res. 2002; 90: 1197-1204Google Scholar, 7Tedgui A. Mallat Z. Circ. Res. 2002; 90: 1145-1146Google Scholar). Although a CD36 signaling pathway has been identified in endothelial cells, where its stimulation by thrombospondin results in kinase activation and programmed cell death (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), a corresponding signaling cascade in mononuclear cells has not been identified. In this article, we report that β-amyloid initiates a pro-inflammatory CD36 signaling cascade in mononuclear cells. We show that β-amyloid induces association of CD36 with the Src phosphotyrosine kinase (PTK) Lyn and activates a signaling cascade involving another Src kinase family member, Fyn, and p44/42 mitogen-activated protein kinase (MAPK). Interruption of this signaling cascade, via chemical inhibitors or targeted disruption of the Src kinases downstream of CD36, results in inhibition of macrophage inflammatory responses to β-amyloid and decreased recruitment of microglia to sites of amyloid injection in vivo. These studies reveal a macrophage activation program initiated by a non-lipid ligand of CD36 that promotes inflammatory changes in response to amyloid proteins that accumulate in Alzheimer's disease and atherosclerosis. A P1 clone containing the murine CD36 locus was obtained from Genome Systems (St. Louis, MO) and used to generate a CD36 targeting vector KO3CD36tm1 (Fig.1 A). The linearized vector was electroporated into 129/SvEv embryonic stem cells. G418-resistant clones were selected and screened for homologous recombination by Southern blot analysis ofEcoRI-digested DNA. Using a probe corresponding to the exon 10 sequence, a clone containing the targeted allele was identified. This embryonic stem cell clone was microinjected into C57BL/6J blastocysts to generate chimeras, which were bred to C57BL/6J female mice to obtain offspring heterozygous for the CD36 targeted allele. F1 CD36 heterozygotes were intercrossed to obtain CD36−/− and wild type littermate control mice. CD14/CD36 double null mice (CD14−/−/CD36−/−) were generated by crossing the CD14−/− mice we had generated previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar) with CD36−/− mice. Lyn−/− and Fyn−/− mice were obtained from the Jackson Laboratories (Bar Harbor, ME). For inhibitor studies, cells were treated with the general Src kinase inhibitor PP1 (5 μm, 45 min; Biomol, Plymouth Meeting, PA). Aβ1–42 and reverse Aβ42–1 (revAβ) peptides were obtained from American Peptide Company (Sunnyvale, CA). To induce fibril formation, Aβ1–42 was resuspended in H2O at 1 mg/ml and incubated for 1 week at 37 °C (10El Khoury J. Hickman S.E. Thomas C.A. Loike J.D. Silverstein S.C. Neurobiol. Aging. 1998; 19: S81-S84Google Scholar, 11El Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google Scholar). Fibril formation was confirmed by thioflavine S (Sigma) fluorescent staining as described previously (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). fAβ and revAβ were used at 40 μm in all studies unless otherwise stated. Elicited peritoneal macrophages were collected from mice 4 days after intraperitoneal injection of 3% thioglycollate as we described previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). Cells adherent after 2 h of culture (>97% F4/80+) were incubated in DMEM with 1% FCS overnight prior to use. Primary microglia were prepared from mixed brain cultures of post-natal day 2 mice as previously described (10El Khoury J. Hickman S.E. Thomas C.A. Loike J.D. Silverstein S.C. Neurobiol. Aging. 1998; 19: S81-S84Google Scholar, 11El Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google Scholar). Briefly, whole brains were incubated in 0.25% trypsin and 1 mm EDTA (10 min, 25 °C) and dissociated to obtain a single-cell suspension. Cells were washed in Hanks' balanced salt solution (four times, 10 min) and cultured in DMEM containing 10% FCS for 10–12 days. Microglia accumulating above astrocyte monolayers were collected after gentle agitation and were routinely >95% CR3+ by flow cytometric analysis. Primary microglia were cultured for 48 h in DMEM containing 0.5% FBS prior to use. Following stimulation, microglia were fixed in 3% paraformaldehyde and stained for phospho-p44/42 according to the manufacturer's protocol (New England Biolabs). Immunoreactivity was detected using the Vectastain Avidin/Biotin ABC kit (Vector Laboratories, Burlingame, CA) and 3,3′-diaminobenzidine. Staining was recorded on a Nikon Eclipse E600 microscope at a fixed exposure setting. Cells were washed in ice-cold PBS and lysed in radioimmune precipitation buffer containing protease and phosphatase inhibitors, and 40 μg of protein was run on 10% denaturing SDS-polyacrylamide gels. Blotted proteins were blocked in 5% nonfat dry milk in Tris-buffered saline containing 0.1% Tween 20, incubated overnight at 4 °C with primary antibody (4G10, mouse anti-phosphotyrosine Ab (Upstate Biotechnology Inc., Lake Placid, and and Ab (New England washed in Tris-buffered saline containing 0.1% Tween 20, incubated with and with were to and were using a μg of protein prepared as described above was incubated with or Ab Biotechnology Inc., CA) overnight at 4 and were with proteins were washed in radioimmune precipitation buffer and resuspended in of of was run on an denaturing SDS-polyacrylamide for of CD36 using a Ab K.J. F. Andersson L.P. D. Freeman M.W. Nat. Med. 2001; Scholar), and 10 was run on a 10% denaturing SDS-polyacrylamide for of Lyn or using a or Ab as described oxygen production was by as we described previously (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). Cells were incubated on in DMEM containing 1% FCS for 1 h and stimulated with 10 μg or 1 mg/ml in Hanks' balanced salt solution containing 1 mg/ml for 10 at 37 of 1 mg/ml was and cells were incubated at 37 °C for 1 production with the formation of a the of which was by microscope (10 and analysis Cells were incubated in DMEM containing 1% FCS for 1 h prior to and stimulated with 10 μg of fAβ, 10 μg of or for were collected and to cell and in was by injection or revAβ was on wild type and Lyn−/− mice as described previously C. D. A. M. Nat. Med. 1998; Scholar). Briefly, mice were with and and in a A was in the 1 mm to and 2 mm to the 2 of fAβ was into the mm from the on the and 2 of revAβ was at the on the of the The mice and The of fAβ and revAβ injection were 48 h mice were by of ice-cold PBS containing The brains were in paraformaldehyde 1 and to 1 The brains were and stained for microglia using a antibody (10 and with to The were washed in PBS, and were using (Vector and at 4 The of microglia at sites of was on by and and of the and staining were at exposure and staining at the of was using analysis To stimulated signal transduction we generated CD36 null mice by targeted in embryonic stem cells as described previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). of the mice CD36 null offspring at the of 1 with or on or We confirmed the of CD36 protein in peritoneal macrophages and primary cultures used in signaling from CD36−/− mice by blot analysis 1 kinases activated in macrophages in response to inflammatory and a critical of the signaling In cultured microglia and macrophages, β-amyloid induces protein of activated signal transduction Landreth J. Neurosci. Scholar). microglia senile plaques for suggesting that signaling events in P. Neurosci. Scholar, F. M. B. Cole G.M. Am. J. Pathol. 1998; Scholar). We β-amyloid stimulation of peritoneal macrophages in the of proteins via engagement of fAβ the accumulation of proteins in wild type macrophages, this was in the peritoneal macrophages from CD36−/− mice 1 These detected by with an anti-phosphotyrosine with of and and were detected at proteins represent potential mediators of a CD36-dependent signaling the of the of proteins was with that of MAP kinase p44/42 as the possibility that β-amyloid of macrophages of in a CD36-dependent was of wild type macrophages with fAβ the activation of p44/42 MAPK, as detected by an antibody for the of the protein A). In phospho-p44/42 protein was detected in treated CD36−/− macrophages, the of of p44/42 2 A). In wild type macrophages, p44/42 by fAβ was and at which that activation of p44/42 MAP kinase is a primary signaling activation of p44/42 was detected in wild type or CD36−/− macrophages stimulated with revAβ the of the response 2 of of p44/42 in wild type and CD36−/− macrophages treated with that p44/42 could be activated by signaling that of CD36 2 To possibility that signaling in wild type macrophages from with LPS, mice the were used as a of cells (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). was in wild type macrophages, phospho-p44/42 in treated with fAβ of stimulation 2 of macrophages null for and CD36 or accumulation of that this signaling response is via We have recently that microglia pro-inflammatory cells to play a role in the pathogenesis of Alzheimer's CD36, and that this can mediate to fAβ (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). To activation of p44/42 by fAβ was CD36-dependent in microglia, was for phospho-p44/42 accumulation in primary microglia from wild type and CD36−/− mice. type microglia staining for phospho-p44/42 at and 10 with fAβ 2 In accumulation of phospho-p44/42 was not in the of treated CD36−/− microglia 2 that β-amyloid initiates p44/42 signaling via CD36 in macrophages and of the Src family of have previously been reported to with CD36 (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), and to be of involved in the activation of MAP we of this family of might previously reported S.C. Landreth J. Neurosci. 2001; 21: Scholar), we that of wild type macrophages with a general inhibitor of Src p44/42 activation by fAβ A). To of the Src family involved in we obtained mice null for or Lyn We on the expressed had previously been reported to with CD36 in endothelial cells (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), Lyn is expressed in cells Annu. Rev. Scholar). The accumulation of phospho-p44/42 was in Fyn−/− and Lyn−/− macrophages as with wild type cells macrophage were shown to of p44/42 protein and to of phospho-p44/42 in response to LPS, that p44/42 is activated by signaling of Lyn and in cells not These that of the Src kinase family may signaling and that the of Lyn or the downstream activation of this signaling To β-amyloid induces the association of Lyn or with CD36, we were generated from macrophages treated with fAβ and used for with antibodies to Lyn or The were and for of of wild type macrophages initiated the recruitment of CD36 to containing Lyn not CD36 was to with Lyn of fAβ suggesting a association of proteins exposure to β-amyloid To that the that was detected in was in CD36 we in treated CD36−/− was detected in from CD36−/− macrophages studies, to the association of CD36 with kinase, to show of CD36 and not These that fAβ initiates the association of CD36 to containing Lyn in a with the downstream activation of p44/42 signaling in β-Amyloid has been reported to the of in and microglia Landreth J. Neurosci. Scholar, J.W. T. J. J. 2001; Scholar), and we have that this is blocked by antibodies to CD36 (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). the role of Lyn and kinase in activation of p44/42 MAPK, we kinases for macrophage production was by and in Lyn−/− and Fyn−/− macrophages, as with wild type macrophages A). A was in CD36−/− macrophages stimulated El J. T. J. M. W. and A. D. for that of proteins is an of signaling pathway to macrophage the of by Lyn−/− and Fyn−/− macrophages in response to another inflammatory was to that in wild type macrophages 4 A). These results that Lyn−/− and Fyn−/− macrophages have a in production in response to fAβ the ability to generate reactive oxygen in response to other β-amyloid induces production of MCP-1, a chemokine that to sites of To production is by a signaling cascade, production in wild and Fyn−/− macrophages was In the of Lyn kinase, production was by 4 This in Lyn−/− macrophages was to that in macrophages CD36 Interestingly, in production was in treated Fyn−/− macrophages, that this kinase is not an in the signaling pathway to production 4 type and Lyn−/− macrophages of in response to and revAβ suggesting that the in production in stimulated with fAβ is to that These the of CD36 and Lyn as a novel signal transduction pathway mediating the production of of Lyn kinase signaling chemokine production in response to fAβ, we used an in to of this signaling pathway recruitment to sites injection has previously been shown to induce the of Alzheimer's disease in and including the recruitment and activation of microglia and of C. D. A. M. Nat. Med. 1998; Scholar, N. Y. 1999; D.T. Rogers J. Neurosci. 1998; Scholar). Using wild type and Lyn−/− we the response to fAβ injection to that of revAβ injection in the as an In wild type injection of fAβ the accumulation of cells with a of microglia 48 h A). the response to fAβ was to revAβ injection in wild type mice as by of at the injection analysis A and in treated Lyn−/− the recruitment of microglia to sites of fAβ was not to sites of revAβ injection and of the of cells at the sites of injection a accumulation of microglia to fAβ in wild type mice in Lyn−/− mice to In in of Lyn signaling not macrophage to wild type microglia not This that the decreased accumulation at sites injection in Lyn−/− brains is to of chemokine production a in the ability of cells to to These that Lyn kinase signaling a role in the response to fAβ in vivo. The activation of microglia at sites of β-amyloid deposition is believed to result in a chronic inflammation that the of Alzheimer's The of pro-inflammatory mediators by macrophages and microglia has been studies have identified signaling events activated by β-amyloid in this cell type Landreth J. Neurosci. Scholar, S.C. Landreth J. Neurosci. 2001; 21: Scholar, J.W. T. J. J. 2001; Scholar, Landreth J. Neurosci. 1999; 19: Scholar, Landreth J. Neurosci. 2000; Scholar, Landreth J. Neurosci. 1998; Scholar), the of a receptor-mediated signaling pathway that responses has been We have identified a pro-inflammatory signaling cascade, by β-amyloid, that mediates the recruitment and activation of mononuclear The CD36 signaling cascade initiated by β-amyloid is in The signaling identified was the association of CD36 with Lyn Although CD36 has been shown to with Lyn in this had not previously been to response M.M. J.W. S. A. Scholar). A role for Lyn in β-amyloid signaling has previously been Landreth J. Neurosci. S.C. Landreth J. Neurosci. 2001; 21: Scholar), the via which Lyn activation at the was not We have that the of CD36 and Lyn in macrophages is for the of downstream p44/42 activation and pro-inflammatory responses to β-amyloid. In we that another of the Src kinase Fyn, to p44/42 activation by β-amyloid. has previously been shown to with CD36 in endothelial cells and is an of the CD36 signaling cascade that thrombospondin inhibition of (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar). In endothelial cells, the activation of another family member, and this signaling initiates programmed cell we were to a association of CD36 with in is that in macrophages, a cell type in which Lyn is CD36 with Although an of this signaling its with CD36 may be We show that of Lyn or kinase signaling inhibits macrophage inflammatory responses in the of Lyn kinase signaling results in accumulation of microglia at sites of β-amyloid accumulation in the Using the of injection of fAβ, we have in accumulation in the brains of mice In that signal transduction an role in the inflammatory response to this Atherosclerosis, like Alzheimer's disease, is associated with pathologic changes in chronic inflammatory CD36 has been postulated to play a critical role in the initiation of atherosclerotic lesions through its ability to bind and internalize modified low density lipoprotein trapped in the artery wall, facilitating the formation of lipid-engorged macrophage cells G. J. Scholar, Febbraio M. N. D. Silverstein R.L. Hajjar D.P. J. Clin. Invest. 2000; Scholar) (5Ross R. N. Engl. J. Med. 1999; 340: 115-126Google Scholar). studies in mice CD36 a role for this in In its atherosclerotic formation was by as as M. J.D. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2000; Scholar). is the in atherosclerosis in the CD36 null mouse was a of macrophage lipid accumulation or of signaling events might have to the the finding that β-amyloid is in advanced human atherosclerotic lesions, an or pathway for CD36 activation in atherosclerotic plaques is (6De Meyer G.R. De Cleen D.M. Cooper S. Knaapen M.W. Jans D.M. Martinet W. Herman A.G. Bult H. Kockx M.M. Circ. Res. 2002; 90: 1197-1204Google Scholar, 7Tedgui A. Mallat Z. Circ. Res. 2002; 90: 1145-1146Google Scholar). Although other scavenger including and have been to be involved in atherosclerosis and Alzheimer's disease Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google H. M. H. H. T. S. S. G. S. N. Invest. 1998; Scholar, H. Y. M. N. M. H. T. T. Y. Y. Y. M. H. H. T. A. S. T. Y. H. Y. T. Scholar), ligand engagement of CD36 may be of its ability to a pro-inflammatory signaling pathway (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar). CD36 is a of the scavenger family of These proteins that the of binding of with This that other proteins that fibrillar might this pathway and responses that contribute to chronic the we report with β-amyloid the possibility that CD36 engagement by non-lipid ligands could play a role in Alzheimer's disease and via the chronic activation of mononuclear We from the for the of and from the for with of