Microglial transplantation increases amyloid‐β clearance in Alzheimer model rats

Takata, Kazuyuki; Kitamura, Yoshihisa; Yanagisawa, Daijiro; Morikawa, Shigehiro; Morita, Masahito; Inubushi, Toshiro; Tsuchiya, Daiju; Chishiro, Saori; Saeki, Mana; Taniguchi, Takashi; Shimohama, Shun; Tooyama, Ikuo

doi:10.1016/j.febslet.2007.01.009

Cited by 95 publications

(68 citation statements)

References 26 publications

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“…Activated microglia have been observed around senile plaques in the brains of AD patients 38,39) and in fact microglia are activated by fibril Aβ. 40) Although microglia are usually in a state of rest and do not damage neurons and tissue, activated microglia can induce neuronal cell and tissue injury by inducing inflammation via the release of inflammatory cytokines, including tumor necrosis factor α and interleukin-1 (IL-1).…”

Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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Amyloid-beta peptide 1-42 (Aβ42) plays a key role in the neurotoxicity found in Alzheimer's disease. Mononuclear phagocytes in the brain (microglia), can potentially clear Aβ via phagocytosis. Recently, the shuttling-protein nucleolin has been shown to possess scavenger receptor-activity. Here, we investigated whether this receptor interacts specifically with Aβ type 1-42 and mediates its phagocytosis by microglia. While monomeric and fibril Aβ42 were phagocytosed by mouse microglial EOC2 cells, amyloid β peptide 1-40 (Aβ40) was only weakly phagocytosed. Surface plasmon-resonance analysis revealed that nucleolin strongly associates with Aβ42, but only weakly associates with Aβ40. Immunofluorescence staining of antinucleolin antibody revealed that EOC2 cells and rat primary microglia express nucleolin on their cell surfaces. Further, pretreating EOC2 cells with anti-nucleolin antibody, but not immunoglobulin G (IgG), inhibited phagocytosis of monomeric Aβ42 by microglia. Additionally, nucleolin-transfected HEK293 cells phagocytosed monomeric and fibril Aβ42 but not monomeric and fibril Aβ40. Moreover, AGRO, a nucleolin-specific oligonucleotide aptamer, inhibited phagocytosis of monomeric and fibril Aβ42, but not monomeric and fibril Aβ40. These results indicate that nucleolin is a receptor that allows microglia to recognize monomeric and fibril Aβ42.

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Section: Discussionmentioning

confidence: 99%

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Ozawa

Nakamura

Koike

et al. 2013

Biological & Pharmaceutical Bulletin

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“…Animals were monitored until they regained full consciousness. Three days after injection of cells, the mice were terminally anesthetized with Avertin and perfused with heparinized saline (2500 IU/L) for 2 min (Takata et al, 2007;Pihlaja et al, 2008). The brains were removed and frozen in liquid nitrogen and stored at Ϫ80°C until sectioning.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Zhao

Su²,

Bales³

et al. 2009

J. Neurosci.

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Recent studies suggest that bone marrow-derived macrophages can effectively reduce ␤-amyloid (A␤) deposition in brain. To further elucidate the mechanisms by which macrophages degrade A␤, we cultured murine macrophages on top of A␤ plaque-bearing brain sections from transgenic mice expressing PDAPP [human amyloid precursor protein (APP) with the APP 717VϾF mutation driven by the platelet-derived growth factor promoter]. Using this ex vivo assay, we found that macrophages from wild-type mice very efficiently degrade both soluble and insoluble A␤ in a time-dependent manner and markedly eliminate thioflavine-S positive amyloid deposits. Because macrophages express and secrete apolipoprotein E (apoE), we compared the efficiency of A␤ degradation by macrophages prepared from apoE-deficient mice or mice expressing human apoE2, apoE3, or apoE4. Macrophages expressing apoE2 were more efficient at degrading A␤ than apoE3-expressing, apoE4-expressing, or apoE-deficient macrophages. Moreover, macrophage-induced degradation of A␤ was effectively blocked by an anti-apoE antibody and receptor-associated protein, an antagonist of the low-density lipoprotein (LDL) receptor family, suggesting involvement of LDL receptors. Measurement of matrix metalloproteinase-9 (MMP-9) activity in the media from human apoE-expressing macrophages cocultured with A␤-containing brain sections revealed greater levels of MMP-9 activity in apoE2-expressing than in either apoE3-or apoE4-expressing macrophages. Differences in MMP-9 activity appear to contribute to the isoform-specific differences in A␤ degradation by macrophages. These apoE isoform-dependent effects of macrophages on A␤ degradation suggest a novel "peripheral" mechanism for A␤ clearance from brain that may also, in part, explain the isoformdependent effects of apoE in determining the genetic risk for Alzheimer's disease.

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“…These findings suggest the potential of exogenous microglia for the cell therapeutic approach in AD. Therefore, we transplanted rat primary cultured microglia into the lateral ventricle of the Aβ-injected rat and found that exogenous microglia accumulated on the Aβ deposits and increased Aβ clearance in the brain of Aβ-injected rat (53). In the study, we transplanted microglia into the lateral ventricle, while Sawada's groups reported that intra-arterially injected microglia but not macrophages can migrate through the intact or injured blood-brain barrier (BBB) to the brain parenchyma (54,55).…”

Section: Microglial Accumulation On Aβ Depositions In Ad Brainsmentioning

confidence: 99%

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Tangle Formation, Amyloid-β, and Microglia in Alzheimer’s Disease

Takata

Kitamura

2012

J Pharmacol Sci

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Abstract. Pathological hallmarks of Alzheimer's disease (AD) include senile plaques, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaques are composed of amyloid-β (Aβ) and are surrounded by microglia, a primary immune effector cell in the central nervous system. NFTs are formed by the intraneuronal accumulation of hyperphosphorylated tau, and progressive synaptic and neuronal losses closely correlate with cognitive deficits in AD. Studies on responsible genes of familial AD and temporal patterns of pathological changes in brains of patients with Down's syndrome (Trisomy 21), who invariably develop neuropathology of AD, have suggested that Aβ accumulation is a primary event that influences other AD pathologies. Although details of the interaction between AD pathologies remain unclear, experimental evidences to discuss this issue have been accumulated. In this paper, we review and discuss recent findings that link the AD pathologies to each other. Further studies on the interaction between pathologies induced in AD brain may contribute to provide deep insight into the pathogenesis of AD and to develop novel therapeutic, prophylactic, and early diagnostic strategies for AD.

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Microglial transplantation increases amyloid‐β clearance in Alzheimer model rats

Cited by 95 publications

References 26 publications

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Shuttling Protein Nucleolin Is a Microglia Receptor for Amyloid Beta Peptide 1-42

Macrophage-Mediated Degradation of β-Amyloid via an Apolipoprotein E Isoform-Dependent Mechanism

Molecular Approaches to the Treatment, Prophylaxis, and Diagnosis of Alzheimer’s Disease: Tangle Formation, Amyloid-β, and Microglia in Alzheimer’s Disease

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