Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer's disease and amyotrophic lateral sclerosis

Akiyama, Haruhiko; Nishimura, Tōru; Kondo, Hiromi; Ikeda, Kenji; Hayashi, Yokichi; McGeer, Patrick L.

doi:10.1016/0006-8993(94)91779-5

Cited by 142 publications

(106 citation statements)

References 13 publications

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“…1 f and j, respectively). That M-CSF might contribute to the pathogenesis of AD was suggested by the presence of c-fms, the receptor for M-CSF (38) on microglia (39) (Fig. 1 g and h; show double immunostaining of microglia for c-fms and CD68, respectively), which was absent in age-matched controls (data not shown).…”

Section: Resultsmentioning

confidence: 93%

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Yan

Zhu²,

Fu³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

385

153

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In Alzheimer disease (AD), neurons are thought to be subjected to the deleterious cytotoxic effects of activated microglia. We demonstrate that binding of amyloidbeta peptide (A␤) to neuronal Receptor for Advanced Glycation Endproduct (RAGE), a cell surface receptor for A␤, induces macrophage-colony stimulating factor (M-CSF) by an oxidant sensitive, nuclear factor B-dependent pathway. AD brain shows increased neuronal expression of M-CSF in proximity to A␤ deposits, and in cerebrospinal fluid from AD patients there was Ϸ5-fold increased M-CSF antigen (P < 0.01), compared with age-matched controls. M-CSF released by A␤-stimulated neurons interacts with its cognate receptor, c-fms, on microglia, thereby triggering chemotaxis, cell proliferation, increased expression of the macrophage scavenger receptor and apolipoprotein E, and enhanced survival of microglia exposed to A␤, consistent with pathologic findings in AD. These data delineate an inflammatory pathway triggered by engagement of A␤ on neuronal RAGE. We suggest that M-CSF, thus generated, contributes to the pathogenesis of AD, and that M-CSF in cerebrospinal fluid might provide a means for monitoring neuronal perturbation at an early stage in AD.

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Section: Resultsmentioning

confidence: 93%

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Yan

Zhu²,

Fu³

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

385

153

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“…Increased M-CSFR expression by microglia has been reported on activated microglia after ischemic and mechanical brain injury in mice (14,15). Furthermore, the M-CSFR is increased on microglia in AD brain, suggesting that overexpression of this receptor is integral to AD pathophysiology (16).…”

mentioning

confidence: 97%

“…We recently demonstrated increased expression of M- CSFR, encoded by c-fms, on activated microglia in the APP V717F transgenic mouse model for AD (13). Expression of M-CSFR is also increased on microglia in AD brain (16), and after experimental ischemic or traumatic brain injury (14, 15). Our results suggest that increased expression of c-fms may be an important component of the molecular pathway leading to microglial proliferation, cytokine expression, and nitric oxide production in these diverse forms of neurologic insult.…”

Section: Induction Of Il-1␣ In Organotypic Hippocampal Slices After Cmentioning

confidence: 99%

Overexpression of Macrophage Colony-stimulating Factor Receptor on Microglial Cells Induces an Inflammatory Response

Mitrasinovic

Perez

Zhao

et al. 2001

Journal of Biological Chemistry

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Microglia are important in the inflammatory response in Alzheimer's disease (AD). We showed previously that macrophage colony-stimulating factor receptor (M-CSFR), encoded by the c-fms protooncogene, is overexpressed on microglia surrounding amyloid ␤ (A␤) deposits in the APP V717F mouse model for AD. The M-CSFR is also increased on microglia after experimental brain injury and in AD. To determine the relevance of these findings, we transiently expressed M-CSFR on murine BV-2 and human SV-A3 microglial cell lines using an SV40-promoted c-fms construct. M-CSFR overexpression resulted in microglial proliferation and increased expression of inducible nitric-oxide synthase, the proinflammatory cytokines interleukin-1␣, macrophage inflammatory protein 1-␣, and interleukin-6 and of macrophage colony-stimulating factor (M-CSF) itself. Antibody neutralization of M-CSF showed that the M-C-SFR-induced proinflammatory response was dependent on M-CSF in the culture media. By using a co-culture of c-fms-transfected murine microglia and rat organotypic hippocampal slices and a species-specific real time reverse transcriptase-polymerase chain reaction assay and enzyme-linked immunosorbent assay, we showed that M-CSFR overexpression on exogenous microglia induced expression of interleukin-1␣ by the organotypic culture. These results show that increased M-CSFR expression induces microglial proliferation, cytokine expression, and a paracrine inflammatory response, suggesting that in APP V717F mice increased M-CSFR on microglia could be an important factor in A␤-induced inflammatory response.

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“…A distinctive phenotypic feature of microglia surrounding A␤ plaques in APPV717F transgenic mice and in AD is enhanced expression of the macrophage colony-stimulating factor receptor (M-CSFR), translation product of the c-fms proto-oncogene (10,11). Microglial M-CSFR expression is also increased after experimental ischemic and traumatic brain injury (12,13).…”

mentioning

confidence: 99%

Accelerated Phagocytosis of Amyloid-β by Mouse and Human Microglia Overexpressing the Macrophage Colony-stimulating Factor Receptor

Mitrasinovic

Murphy

2002

Journal of Biological Chemistry

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Alzheimer's disease (AD) 1 is characterized by amyloid-␤ peptide (A␤) plaques surrounded by microglia. A␤ is thought to be directly neurotoxic, and activated microglia are hypothesized to have negative effects on neurons through the release of effectors of inflammation (1). However, as brain macrophages microglia can clear A␤ by phagocytosis, primarily through macrophage scavenger receptors (MSR) (2-6). Immunization of transgenic mice modeling AD with A␤ results in clearance of plaques from the brain (7). Whereas some results suggest that microglial phagocytosis may be key in clearance of A␤ after immunization (8), other findings indicate that circulating antibodies may result in movement of A␤ out of the brain (9). This controversy has stimulated renewed interest in uptake of A␤ by microglia.A distinctive phenotypic feature of microglia surrounding A␤ plaques in APPV717F transgenic mice and in AD is enhanced expression of the macrophage colony-stimulating factor receptor (M-CSFR), translation product of the c-fms proto-oncogene (10, 11). Microglial M-CSFR expression is also increased after experimental ischemic and traumatic brain injury (12, 13). M-CSFR regulates proliferation, activation, and survival of cells in the monocyte-macrophage lineage through tyrosine kinase activation of diverse signal transduction pathways including: Src kinase, Ras-ERK, phosphoinositide 3-kinase, and p38 MAP kinase (14 -16). Deletion of M-CSFR expression results in decreased numbers of cells of the mononuclear phagocyte lineage (17). In AD macrophage colony-stimulating factor (M-CSF), the ligand for M-CSFR expressed by neurons and glia is also increased (18). Simultaneous increases in M-CSF and M-CSFR expression in the brain could result in significant changes in microglial function.We recently demonstrated that overexpression of M-CSFR by cultured microglia increases proliferation, stimulates release of pro-inflammatory and chemotactic cytokines, and induces a paracrine inflammatory response in a microglial-organotypic co-culture system (19). In the present study we sought to determine the effects of M-CSFR overexpression on A␤ phagocytosis by cultured mouse and human microglia. We hypothesized that M-CSFR-induced activation of microglia would increase their capacity to clear A␤ from culture medium. Although A␤ immunization clinical trials have been discontinued in humans for the present, identifying factors that enhance microglial clearance of A␤ may be of benefit in devising alternative means of decreasing A␤ burden in the brain in AD. EXPERIMENTAL PROCEDURES Microglial Cell Lines, Plasmid Transfections, and Tissue culture-The c-fms expression plasmid pTK1 was a gift from Dr. Rao Tekmal (Emory University, Atlanta, GA), and contains the complete mouse c-fms sequence under the control of an SV40 promoter (20). Transfections were carried out using mouse BV-2 and human SV-A3 microglial cells. The BV-2 immortalized microglial cell line has been characterized previously (21)(22)(23)(24). Because of phenotypic changes that occur at...

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Expression of the receptor for macrophage colony stimulating factor by brain microglia and its upregulation in brains of patients with Alzheimer's disease and amyotrophic lateral sclerosis

Cited by 142 publications

References 13 publications

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Amyloid-β peptide–Receptor for Advanced Glycation Endproduct interaction elicits neuronal expression of macrophage-colony stimulating factor: A proinflammatory pathway in Alzheimer disease

Overexpression of Macrophage Colony-stimulating Factor Receptor on Microglial Cells Induces an Inflammatory Response

Accelerated Phagocytosis of Amyloid-β by Mouse and Human Microglia Overexpressing the Macrophage Colony-stimulating Factor Receptor

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