Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis.

Tennent, Glenys A.; Lovat, Laurence; Pepys, MB

doi:10.1073/pnas.92.10.4299

Cited by 376 publications

(251 citation statements)

References 40 publications

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“…Neither were these proto®brils resistant to trypsin treatment in the presence of the protease resistant SAP, in agreement with our EM results that showed no binding of SAP to these structures. Therefore, SAP is seemingly not necessary for the initiation of amyloid ®brillogenesis, but may stabilize and protect mature ®brils [15]. The ®nding that development of amyloidosis in SAP-de®cient mice was delayed compared to in normal mice [16,17] is compatible with the interpretation of our data.…”

Section: Discussionsupporting

confidence: 88%

Localization of Human Serum Amyloid P Component and Heparan Sulfate Proteoglycan in In Vitro‐Formed Aβ Fibrils

Nielsen¹,

Nybo

Junker

et al. 2000

Scand J Immunol

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Ultrastructural studies of the localization of serum amyloid P component (SAP) in amyloid ®brils have given divergent results. We here report for the ®rst time that electron microscopy of SAP coincubated with Ab 1±42 peptides or with mature Ab 1±42 ®brils, revealed SAP molecules coating the surface of the mature ®brils and that proto®brils of Ab 1±42 did not bind SAP. Also when incubated with extracted amyloid light chain (AL)-®brils the SAP molecules aligned on the ®bril surface. Heparan sulfate proteoglycan bound to the surface of the Ab ®brils with a spacing of about 50 nm. We conclude that SAP does not bind to proto®brils but to the surface of mature Ab ®brils and that it may stabilize and protect the ®brils.

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Section: Discussionsupporting

confidence: 88%

Localization of Human Serum Amyloid P Component and Heparan Sulfate Proteoglycan in In Vitro‐Formed Aβ Fibrils

Nielsen¹,

Nybo

Junker

et al. 2000

Scand J Immunol

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“…87 Furthermore, it has been shown that SAP inhibits the degradation of several types of amyloid fibrils by proteases. Tennent et al 88 suggested that SAP protects amyloid from proteolytic degradation in vivo by binding to fibrils and masking fibrillar conformation.…”

Section: Serum Amyloid P Componentmentioning

confidence: 99%

“…98 Similarly, the calcium-dependent binding of SAP to amyloid fibrils formed from A, serum amyloid A protein or immunoglobulin light chain, protected the fibrils from subsequent proteasemediated degradation. 88 This in turn led to suggestions that SAP may promote the persistence of amyloid deposits in vivo. For some protein substrates, at low clusterin:substrate ratios (1:50-1:500), clusterin promoted the formation of aggregates with an increased level of thioflavin T fluorescence, suggesting that (at these ratios) it promoted the formation of fibrils from calcitonin, -synuclein and A.…”

Section: Effects Of Ecs On Amyloid Formation In Vitromentioning

confidence: 99%

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

2008

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The in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. Keywords: Extracellular chaperones, receptor-mediated endocytosis, amyloid, protein quality control, aggregate toxicity, fibril formation word statement (for Contents list) plus graphic (note -colour version of below graphic provided separately)Newly identified abundant extracellular chaperones (ECs) may protect the body against dangerously hydrophobic proteins/peptides. This review proposes that ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. SUMMARYThe in vivo formation of fibrillar proteinaceous deposits called amyloid is associated with more than 40 serious human diseases, collectively referred to as protein deposition diseases. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is presented suggesting an important regulatory role for ECs in amyloid formation and disposal in the body. A model is presented which proposes that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific cell receptors for uptake and subsequent degradation. Thus ECs and their receptors may be critical parts of a quality control system to protect the body against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…Control fibrils were isolated from the amyloidotic spleen of a wild hare (Lepus europaeus) [20]. All preparations displayed characteristic red-green dichroism in cross-polarized light microscopy (DMR XA2-QWIN; Leica Microsystems, Milton Keynes, UK) after staining with alkaline alcoholic Congo red [21,22], a fibrillar ultrastructure by negative stain transmission electron microscopy [23] and specific binding by serum amyloid P component [24,25]; their purity and protein content were analysed by reduced SDS-PAGE (ExcelGels; GE Healthcare, Chalfont St. Giles, UK) [16].…”

Section: Amyloid Fibrilsmentioning

confidence: 99%

Disease‐associated prion protein is not detectable in human systemic amyloid deposits

Tennent

Head

Bishop

et al. 2007

The Journal of Pathology

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Cerebral and cardiac amyloid deposits have been reported after scrapie infection in transgenic mice expressing variant prion protein (PrP C ) lacking the glycophosphatidylinositol anchor. The amyloid fibril protein in the systemic amyloid deposits was not characterized, and there is no clinical or pathological association between prion diseases and systemic amyloidosis in humans. Nevertheless, in view of the potential clinical significance of these murine observations, we tested both human amyloidotic tissues and isolated amyloid fibrils for the presence of PrP Sc , the prion protein conformation associated with transmissible spongiform encephalopathy (TSE). We also sequenced the complete prion protein gene, PRNP, in amyloidosis patients. No specific immunohistochemical staining for PrP Sc was obtained in the amyloidotic cardiac and other visceral tissues of patients with different types of systemic amyloidosis. No protease-resistant prion protein, PrP res , was detectable by Western blotting of amyloid fibrils isolated from cardiac and other systemic amyloid deposits. Only the complete normal wild-type PRNP gene sequence was identified, including the usual distribution of codon 129 polymorphisms. These reassuringly negative results do not support the idea that there is any relationship of prions or TSE with human systemic amyloidosis, including cardiac amyloid deposition.

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Serum amyloid P component prevents proteolysis of the amyloid fibrils of Alzheimer disease and systemic amyloidosis.

Abstract: Extracellular deposition of amyloid fibrils is responsible for the pathology in the systemic amyloidoses and probably also in Alzheimer disease [Haass, C.

Cited by 376 publications

References 40 publications

Localization of Human Serum Amyloid P Component and Heparan Sulfate Proteoglycan in In Vitro‐Formed Aβ Fibrils

Localization of Human Serum Amyloid P Component and Heparan Sulfate Proteoglycan in In Vitro‐Formed Aβ Fibrils

Potential roles of abundant extracellular chaperones in the control of amyloid formation and toxicity

Disease‐associated prion protein is not detectable in human systemic amyloid deposits

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