Microglial Cells Internalize Aggregates of the Alzheimer's Disease Amyloid β-Protein Via a Scavenger Receptor

Paresce, Donata M.; Ghosh, Rahul; Maxfield, Frederick R.

doi:10.1016/s0896-6273(00)80187-7

Cited by 623 publications

(501 citation statements)

References 62 publications

Supporting

Mentioning

482

Contrasting

Unclassified

Order By: Relevance

“…Consistent with a mechanism involving membrane receptors, we have shown that the lectin ConA, which forms clusters of membrane glycoproteins on the cell surface, also causes neurodegeneration and apoptotic death in cultured neurons similar to that observed with A␤ while succinyl ConA, which binds but does not cross-link, is inactive (39). Recently, Burdick,et al (40) have shown that a substantial portion of the A␤ that binds to cells can be removed by treatment with trypsin and several receptors that appear to bind A␤ peptides have been identifed (41)(42)(43)(44)(45)(46). In the case of the receptor for advanced glycation end products (RAGE), some evidence has been presented that it may be directly involved in A␤-induced neurotoxicity (45).…”

Section: Discussionmentioning

confidence: 74%

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Cribbs

Pike²,

Weinstein³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

The amyloidogenic peptide ␤-amyloid has previously been shown to bind to neurons in the form of fibrillar clusters on the cell surface, which induces neurodegeneration and activates a program of cell death characteristic of apoptosis. To further investigate the mechanism of A␤ neurotoxicity, we synthesized the all-D-and all-Lstereoisomers of the neurotoxic truncated form of A␤ (A␤ [25][26][27][28][29][30][31][32][33][34][35] ) and the full-length peptide (A␤ 1-42 ) and compared their physical and biological properties. We report that the purified peptides exhibit nearly identical structural and assembly characteristics as assessed by high performance liquid chromatography, electron microscopy, circular dichroism, and sedimentation analysis. In addition, both enantiomers induce similar levels of toxicity in cultured hippocampal neurons. These data suggest that the neurotoxic actions of A␤ result not from stereoisomer-specific ligand-receptor interactions but rather from A␤ cellular interactions in which fibril features of the amyloidogenic peptide are a critical feature. The promiscuous nature of these ␤-sheet-containing fibrils suggests that the accumulation of amyloidogenic peptides in vivo as extracellular deposits represents a site of bioactive peptides with the ability to provide inappropriate signals to cells leading to cellular degeneration and disease.Alzheimer's disease (AD), 1 vascular dementia, and hereditary cerebral hemorrhage with the Dutch type are diseases that share an invariant pathological feature, the accumulation of an amyloidogenic peptide into insoluble fibrillar extracellular deposits. In all three cases, the major component of the extracellular debris is the ␤-amyloid peptide (A␤) that is derived from the proteolytic processing of the large membraneanchored amyloid precursor protein (APP) encoded by a single gene located on chromosome 21 (1). However, the biological significance of these amyloid deposits has been extensively debated as to whether they are a causative factor of each disease or merely a metabolically inert end product lacking in biological activity. Evidence in support of a causative role for A␤ in neuropathology comes from genetic analysis of the APP gene where several autosomal dominant mutations have been linked with AD and hereditary cerebral hemorrhage with the Dutch type (2, 3). In a recent in vitro study, the ␤-APP 717 mutation consistently caused a significant increase in the percentage of the longer and more amyloidogenic A␤ 1-42 over the shorter A␤ 1-40 (4). Incorporation of this same mutation into a transgenic mouse model yields A␤ deposition and neuropathology that closely parallels that observed in AD (5). Additional in vivo evidence suggesting that the A␤ peptide itself may be biologically active comes from a transgenic model overexpressing A␤ , in which A␤ transgene expression was detected in a variety of peripheral tissues but histopathological changes were restricted to the brain. Moreover, the neurodegeneration was largely limited to the cerebral cortex, ...

show abstract

Section: Discussionmentioning

confidence: 74%

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Cribbs

Pike²,

Weinstein³

et al. 1997

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…We propose that failure of microglia to stem the tide of neuronal degeneration and Aβ deposition in AD is the result of the concomitant overexpression of cytokines, such as IL-1, which not only set in motion neurodegenerative cascades but also induce further microglial activation. The inability of microglia to sufficiently clear debris in AD, including fDNA as shown here, may be responsible, at least in part, for the apparently continuous activation of microglia, overexpressing IL-1, in AD, thus ensuring a constant source of cytokines and other factors that foster neurodegeneration (Barger and Harmon, 1997;Giulian et al, 1995;Li et al, 2000;Meda et al, 1995;Paresce et al, 1996). Our finding that some microglia had TUNEL-positive cytoplasm as well as TUNEL positive-nuclei suggests that activation of microglia, together with the act of taking up fDNA, leads to the death of microglia.…”

Section: Discussionmentioning

confidence: 94%

“…Multiple scavenger microglial receptors are proposed mediators of such clearance as they promote microglial adhesion to fibrillar Aβ-containing surfaces (El Khoury et al, 1996) and ingestion of Aβ (Paresce et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Microglial activation by uptake of fDNA via a scavenger receptor

Liu

et al. 2004

Journal of Neuroimmunology

View full text Add to dashboard Cite

The fate of the fragmented DNA (fDNA) observed in neuronal nuclei in Alzheimer brain is unknown. However, its fate is suggested as fDNA is found in the cytoplasm of adjacent activated microglia. After a brief incubation with fDNA, approximately 70% of microglia had fDNA in their cytoplasm, were activated, and overexpressed interleukin-1β. Microglial activation enhanced uptake whereas blocking scavenger receptors suppressed this uptake. These results suggest that the brain rids itself of fDNA from dying neurons through microglial uptake, activation, and overexpression of IL-1. Such overexpression of IL-1 in Alzheimer brain has been linked to Alzheimer pathogenesis.

show abstract

“…Pre-aggregated A␤ can be modestly phagocytosed by microglial class A scavenger receptor and the class B scavenger receptors B1 and CD36 [5,8,9,42,50], but when opsonized, it is more aggressively phagocytosed by Fc receptors and complement receptors [53]. Phagocytosis activates the cells, and A␤ binding to the RAGE (receptor for advanced glycation end-products) is also a powerful activator of microglial inflammation [69].…”

Section: Microglia As Phagocytesmentioning

confidence: 99%

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

D’Andrea

Cole

Ard

2004

Neurobiology of Aging

195

131

View full text Add to dashboard Cite

Alzheimer disease (AD) involves glial inflammation associated with amyloid plaques. The role of the microglial cells in the AD brain is controversial, as it remains unclear if the microglia form the amyloid fibrils of plaques or react to them in a macrophage-phagocytic role. Also, it is not known why microglia are preferentially associated with some amyloid plaque types. This review will provide substantial evidence to support the phagocytic role of microglia in the brain as well as explain why microglia are generally associated with specific plaque types that may be explained through their unique mechanisms of formation. In summary, the data presented suggests that plaque associated microglial activation is typically subsequent to specific amyloid plaque formations in the AD brain.

show abstract

Microglial Cells Internalize Aggregates of the Alzheimer's Disease Amyloid β-Protein Via a Scavenger Receptor

Cited by 623 publications

References 62 publications

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

All-D-Enantiomers of β-Amyloid Exhibit Similar Biological Properties to All-L-β-Amyloids

Microglial activation by uptake of fDNA via a scavenger receptor

The microglial phagocytic role with specific plaque types in the Alzheimer disease brain

Contact Info

Product

Resources

About