Direct Evidence for SAA Deposition in Tissues During Murine Amyloidogenesis

Yakar, Shoshana; Kaplan, Batia; Livneh, Avi; Martin, Brian M.; Miura, Katsutoshi; Ali‐Khan, Z.; Shtrasburg, Shmuel; Pras, Mordechai

doi:10.1111/j.1365-3083.1994.tb03519.x

Cited by 20 publications

(11 citation statements)

References 30 publications

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“…Whether degradation in HCHWA-D vessels occurs before or after the deposition of full-length A␤ remains to be addressed. In light of other amyloidoses in which intact as well as aminoand carboxyl-terminal truncated forms of soluble amyloid precursors are consistently present in the affected tissues, it seems likely that deposition precedes digestion (31). However, the finding of amino-and carboxyl-terminal heterogeneity in A␤ from non-AD cerebrospinal fluid (32) also suggests that it may be partially cleaved in the circulation.…”

Section: Fig 5 Mass Spectrometry Of Purified Cortical Vascular A␤mentioning

confidence: 81%

The length of Amyloid-β in Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch Type

Castaño¹,

Prelli²,

Soto

et al. 1996

Journal of Biological Chemistry

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In hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), a genetic variant (E22Q) of amyloid ␤ (A␤) accumulates predominantly in the small vessels of leptomeninges and cerebral cortex, leading to fatal strokes in the fifth or sixth decade of life. A␤ deposition in the neuropil occurs mainly in the form of preamyloid, Congo red negative deposits, while mature neuritic plaques and neurofibrillary tangles, hallmark lesions in Alzheimer's disease (AD), are characteristically absent. A recent hypothesis regarding the pathogenesis of AD states that A␤ extending to residues 42-43 (as opposed to shorter species) can seed amyloid formation and trigger the development of neuritic plaques followed by neuronal damage in AD. We characterized biochemically and immunohistochemically A␤ from three cases of HCHWA-D to determine its length in vascular and parenchymal deposits. Mass spectrometry of formic acid-soluble amyloid, purified by size-exclusion gel chromatography, showed that A␤ 1-40 and its carboxyl-terminal truncated derivatives were the predominant forms in leptomeningeal and cortical vessels. A␤ 1-42 was a minor component in these amyloid extracts. Immunohistochemistry with antibodies S40 and S42, specific for A␤ ending at Val-40 or Ala-42, respectively, were consistent with the biochemical data from vascular amyloid. In addition, parenchymal preamyloid lesions were specifically stained with S42 and were not labeled by S40, in agreement with the pattern reported for AD, Down's syndrome, and aged dogs. Our results suggest that in HCHWA-D the carboxyl-terminal A␤ heterogeneity is due to limited proteolysis in vivo. Moreover, they suggest that A␤ species ending at Ala-42 may not be critical for the seeding of amyloid formation and the development of AD-like neuritic changes.Hereditary cerebral hemorrhage with amyloidosis, Dutch type (HCHWA-D), 1 is an autosomal dominant form of cerebral amyloidosis clinically defined by recurrent strokes and fatal cerebral bleeding in the fifth or sixth decade of life (1). Amyloid deposits are preferentially localized in the walls of small arteries of the leptomeninges and cerebral cortex. Parenchymal deposition is largely in the form of preamyloid lesions or diffuse plaque-like structures that are Congo red-negative and lack the dense amyloid cores commonly present in Alzheimer's disease (AD). Immature or early plaques are occasionally found surrounded by dystrophic neurites, although neurofibrillary tangles are consistently absent (2).Biochemically, HCHWA-D amyloid fibrils are composed of a genetic variant of amyloid ␤ (A␤) of AD and Down's syndrome (3, 4) in which there is a glutamine (Gln) for glutamic acid (Glu) at position 22 due to a missense mutation (cytosine for guanine) at codon 693 of the ␤ precursor protein (␤PP) 770 gene (5). This mutation is pathogenic since it segregates with the disease (6). Several in vitro studies have shown that Glu 3 Gln substitution yields an A␤ variant that has an abnormal conformation (higher content of ␤-sheet), forms amyloid-lik...

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Section: Fig 5 Mass Spectrometry Of Purified Cortical Vascular A␤mentioning

confidence: 81%

The length of Amyloid-β in Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch Type

Castaño¹,

Prelli²,

Soto

et al. 1996

Journal of Biological Chemistry

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“…4): a. Proteolysis of a non-amyloidotic precursor protein may liberate the fibril protein and facilitate amyloidogenesis. This mechanism occurs in Aβ amyloidosis, which is commonly associated with Alzheimer's disease [63], but as yet there is no evidence to suggest that it accounts for AA amyloidosis since the precursor protein has been shown to be potentially amyloidogenic [84,85]. b. Proteolysis of an amyloidogenic precursor protein may occur before, during or after fibrillogenesis.…”

Section: Proteasesmentioning

confidence: 96%

“…Proteolysis at the C-terminal end may occur after amyloid has been formed and may remove a redundant peptide [4,32,84] (Fig. 4b).…”

Section: Proteasesmentioning

confidence: 98%

Pathology, diagnosis and pathogenesis of AA amyloidosis

2002

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Amyloid is defined as a proteinaceous tissue deposit that shows a typical green birefringence in polarised light after staining with Congo red, the presence of non-branching linear fibrils of indefinite length with an approximate diameter of 10-12 nm and a distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril. Approximately 45% of generalised amyloidoses are secondary or reactive (AA) amyloidosis. Among the causes of AA amyloidosis are rheumatic diseases, idiopathic diseases, inherited diseases, infectious diseases and malignant tumours. Recent decades have provided significant advances in our understanding of the pathology and pathogenesis of AA amyloidosis. Its pathogenesis is multifactorial involving many variables such as primary structure of the precursor protein, acute phase response, the presence of non-fibril proteins (e.g. amyloid P component, apolipoprotein E, glycosaminoglycans, proteoglycans and basement membrane proteins), receptors, lipid metabolism and proteases. Study of the pathogenesis of AA amyloidosis has provided many insights into the nature of conformational diseases, which may help in the understanding of other members of this particularly heterogeneous group of diseases, such as Alzheimer's disease and transmissible spongiform encephalopathies.

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“…SAA bound to HDL is the source of the deposited fibril protein [24,55]. Intact SAA has been found in AA-amyloid deposits [27,43,57] as well as proteolytic fragments, which consist of the aminoterminal two-thirds of SAA [23]. Although the size of the fibril protein is variable, its aminoterminal end rarely differs from that of the precursor protein, and failure of aminoterminal truncation of SAA may be an important step in the pathogenesis of AA-amyloidosis [60].…”

Section: Introductionmentioning

confidence: 99%

Comparison of the binding and endocytosis of high-density lipoprotein from healthy (HDL) and inflamed (HDL SAA ) donors by murine macrophages of four different mouse strains

Röcken

Kisilevsky

1998

Virchows Archiv

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Serum amyloid A (SAA) is a plasma acute phase protein and the precursor of the AA-fibril protein deposited in AA-amyloidosis. SAA is bound mainly to high-density lipoproteins (HDL(SAA)). Previous investigations have demonstrated that peritoneal macrophages (mO) from mice are capable of binding and endocytosing HDL(SAA). This observation may indicate a pathway by which SAA enters the mO and where its intracellular metabolism may be followed by degradation and/or amyloidogenesis. Since binding and internalization defects of lipoproteins may be associated with different diseases, it is possible that mouse strain susceptibility to amyloidosis is associated with qualitative differences in the binding and internalization of HDL(SAA). To test this hypothesis a series of binding and internalization experiments was performed in vitro with mO from four different mouse strains, CD-1, A/J, C57BL/6J and C3H/HeJ, which differ in their susceptibility to AA-amyloidosis. Using colloidal gold-labelled lipoproteins, it was evident by light and electron microscopy that mO from all four mouse strains are capable of binding and internalizing HDL (without SAA) and HDL(SAA). HDL and HDL(SAA) were found in such compartments of the receptor-mediated pathway as coated pits, coated vesicles, endosomes and multivesicular bodies and in lipid droplets; no qualitative differences were observed. Therefore, it is unlikely that a defect in binding and uptake of HDL(SAA) is related to the different susceptibilities of these mouse strains to develop AA-amyloidosis. However, the results do not exclude the possibility that differences in the intracellular processing of SAA following endocytosis of HDL(SAA) is involved in this differing susceptibility.

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Direct Evidence for SAA Deposition in Tissues During Murine Amyloidogenesis

Cited by 20 publications

References 30 publications

The length of Amyloid-β in Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch Type

The length of Amyloid-β in Hereditary Cerebral Hemorrhage with Amyloidosis, Dutch Type

Pathology, diagnosis and pathogenesis of AA amyloidosis

Comparison of the binding and endocytosis of high-density lipoprotein from healthy (HDL) and inflamed (HDL SAA ) donors by murine macrophages of four different mouse strains

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