Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

Huang, Frederick Y.; Buttini, Manuel; Wyss‐Coray, Tony; McConlogue, Lisa; Kodama, Tatsuhiko; Pitas, Robert E.; Mucke, Lennart

doi:10.1016/s0002-9440(10)65489-2

Cited by 61 publications

(45 citation statements)

References 44 publications

(56 reference statements)

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“…Our study links SR-BI to perivascular macrophages and establishes a significant role for SR-BI among other scavenger receptors in AD and CAA (37). Our work supports the hypothesis that SR-BI is involved in amyloid pathology primarily as a modulator of the perivascular macrophage response.…”

Section: Discussionsupporting

confidence: 83%

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

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

119

106

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Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux from the peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-β (Aβ). Here we report that SR-BI mediates perivascular macrophage response and regulates Aβ-related pathology and cerebral amyloid angiopathy in an Alzheimer's mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI +/− , −/− ) resulted in a significant increase in perivascular macrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoprotein AI levels in the mouse brain. Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer's disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI +/− mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning and memory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aβ deposits. Our data suggest that SR-BI reduction impairs the response of perivascular macrophages to Aβ and enhances the Aβ-related phenotype and cerebral amyloid angiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer's disease and cerebral amyloid angiopathy.high-density lipoprotein receptor | dementia

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Section: Discussionsupporting

confidence: 83%

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

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

119

106

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“…Scavenger receptors have been proposed to be the moderator of A␤ phagocytosis [32]. However, studies on scavenger receptor knockout mice indicate that this receptor does not initiate or mediate phagocytosis of A␤ in the brain [20]. On the other hand, in vitro studies suggest that this process may be mediated by microglial complement receptor C1q [7,46].…”

Section: Microglia Internalize/degrade Fibrillar Aβ In Vitro But Not mentioning

confidence: 99%

Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease

Nagele

Węgiel

Venkataraman³

et al. 2004

Neurobiology of Aging

441

281

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“…Although Glabe's group (7) reported that the increase in membrane permeability induced by oligomeric A␤ may be receptor independent, the proposed participant microglial receptors included scavenger receptor class AI/ AII (SRA) (8) and receptor for advanced glycation end products (RAGE) (9). Data provided in studies of SRA knockout mice (10), however, do not support a role for SRA. MG have also long been thought to elicit neuroinflammatory reactions (4,6).…”

Section: A Pathological Hallmark Of Alzheimer's Disease (Ad)mentioning

confidence: 99%

“…(2 g/ml) for 3 h at 37°C and then treated with proteinase K (100 g/ml) at 4°C for 15 min or were untreated, as described in Materials and Methods. Proteins (10 g) in the cell lysate were subjected to Western blot analysis using anti-A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] Ab or anti-␤-actin Ab. Monomer and tetramer A␤ levels were measured by densitometric scanning and the results were plotted (right panel).…”

Section: Selective Uptake As Related To Cd36 Functionmentioning

confidence: 99%

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

Shimizu

Kawahara

Kajizono

et al. 2008

The Journal of Immunology

128

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A hallmark of immunopathology associated with Alzheimer’s disease is the presence of activated microglia (MG) surrounding senile plaque deposition of β-amyloid (Aβ) peptides. Aβ peptides are believed to be potent activators of MG, which leads to Alzheimer’s disease pathology, but the role of MG subtypes in Aβ clearance still remains unclear. In this study, we found that IL-4 treatment of rat primary-type 2 MG enhanced uptake and degradation of oligomeric Aβ1–42 (o-Aβ1–42). IL-4 treatment induced significant expression of the scavenger receptor CD36 and the Aβ-degrading enzymes neprilysin (NEP) and insulin-degrading enzyme (IDE) but reduced expression of certain other scavenger receptors. Of cytokines and stimulants tested, the anti-inflammatory cytokines IL-4 and IL-13 effectively enhanced CD36, NEP, and IDE. We demonstrated the CD36 contribution to IL-4-induced Aβ clearance: Chinese hamster ovary cells overexpressing CD36 exhibited marked, dose-dependent degradation of 125I-labeled o-Aβ1–42 compared with controls, the degradation being blocked by anti-CD36 Ab. Also, we found IL-4-induced clearance of o-Aβ1–42 in type 2 MG from CD36-expressing WKY/NCrj rats but not in cells from SHR/NCrj rats with dysfunctional CD36 expression. NEP and IDE also contributed to IL-4-induced degradation of Aβ1–42, because their inhibitors, thiorphan and insulin, respectively, significantly suppressed this activity. IL-4-stimulated uptake and degradation of o-Aβ1–42 were selectively enhanced in type 2, but not type 1 MG that express CD40, which suggests that the two MG types may play different neuroimmunomodulating roles in the Aβ-overproducing brain. Thus, selective o-Aβ1–42 clearance, which is induced by IL-4, may provide an additional focus for developing strategies to prevent and treat Alzheimer’s disease.

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Elimination of the Class A Scavenger Receptor Does Not Affect Amyloid Plaque Formation or Neurodegeneration in Transgenic Mice Expressing Human Amyloid Protein Precursors

Cited by 61 publications

References 44 publications

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease

IL-4-Induced Selective Clearance of Oligomeric β-Amyloid Peptide1–42 by Rat Primary Type 2 Microglia

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