Amyloid P Research Articles

Human neurons generate C-reactive protein and amyloid P: upregulation in Alzheimer’s disease

C-reactive protein (CRP) and amyloid P (AP) are pentraxins which are associated with many pathological lesions, including the amyloid deposits and neurofibrillary tangles (NFTs) of Alzheimer disease (AD). It has always been assumed that they are generated by liver and delivered to their sites of action by serum. Here we report by in situ hydridization, reverse transcriptase–polymerase chain reaction analysis, Western blotting and immunohistochemistry that the mRNAs and proteins of both CRP and AP are concentrated in pyramidal neurons and are upregulated in affected areas of AD brain. Controlling pentraxin production at the tissue level may be important in reducing inflammatory damage in AD.

The eosinophilic material in adenomatoid odontogenic tumor associated with amyloid protein component

Objective: To investigate the relation between eosinophilic materials and amyloid P (AP) component in adenomatoid odontogenic tumor (AOT). Methods: The expression of amyloid proteins and basement membrane proteins, including type IV collagen, laminin and heparin sulfate proteoglycan (HSPG), in AOT were analyzed by immunohistochemical method. Results: Most eosinophilic droplets among tumor cells and some epithelial cells showed positive stain for AP component. The immunoreactions of type IV collagen and laminin were only found in blood vessels of this tumor. The tumor cells and eosinophilic materials in duct-like structures were constantly unstained for both amyloid and basement membrane proteins. Present results suggest that the nature and composition of eosinophilic droplets may differ from the eosinophilic layer in ductlike structures. This study first demonstrated that the amyloid-like deposition in AOT is associated with AP component by immunohistochemical method. It supported that AP component may be epithelial origin since the AP immunolocalization was found in tumor cells.

Amyloid P immunoreactivity precedes C4d deposition on extracellular neurofibrillary tangles.

Extracellular neurofibrillary tangles (eNFTs) are the insoluble cytoskeletal debris left behind when neurons with intracellular neurofibrillary tangles (iNFTs) die. Reactive microglia and reactive astrocytes gather around eNFTs. Many inflammatory proteins are deposited in their vicinity, including activated components of the classical complement pathway. Agents which are potential activators of the pathway include beta-amyloid protein (A beta) and amyloid P (AP), since these in vitro activators have been reported to be associated with both senile plaques (SPs) and eNFTs. To investigate the apparent order in which these proteins are deposited, we studied by immunohistochemistry the relative association of AP, A beta, and the classical complement protein C4d with eNFTs in Alzheimer's disease (AD), parkinsonism-dementia complex of Guam (lytico-bodig, LB), and elderly non-demented cases. In normal elderly cases with mild tangle development, most but not all eNFTs were AP positive. Substantially fewer eNFTs were C4d positive, and in two of the three cases no eNFTs were A beta positive. In AD and mild LB cases with more extensive tangle development, a high portion of eNFTs were AP positive, and most of them were C4d positive. Only a few were A beta positive. In severe LB cases, with dense tangle development, almost all eNFTs were AP and C4d positive, and a significant number were also A beta positive. AP seems to be deposited early in eNFT exposure and could therefore be a potential activator of the complement pathway, while A beta deposition occurs relatively late in the process, and is therefore unlikely to be responsible.

Association of amyloid P protein with pathology in periodontal tissues

The lesion of chronic periodontitis is characterized by the persistence of perivascular collections of degenerate plasma cells. In this study, immunohistochemical demonstration of amyloid P (AP) component was used to define the distribution of this protein in established periodontitis lesions and in biopsies of non-destructive marginal gingivitis. Quantitative assessment of AP indicated significantly higher levels in periodontitis than in gingivitis for all regions of the tissue. This was associated with pathology as determined by the intensity of plasma cell accumulation and the extent of connective tissue matrix degradation. AP was concentrated in the deep connective tissue areas but perivascular accumulation was also noted, as was deposition associated with nerve bundles and, occasionally, in the extracellular matrix of the lining epithelium. These findings have potential significance in relation to the pathology of chronic periodontitis as AP has been shown to interact in a calcium-dependent manner with a number of ligands including fibronectin, elastic fibres, C-4 binding protein and amyloid fibrils.

Amyloid P component and other acute-phase proteins associated with cerebellar Aβ-deposits in Alzheimer's disease

It is established that amyloid P (AP) component and complement proteins are associated with amyloid β (Aβ)-protein deposits in the cerebral cortex of Alzheimer's disease (AD) subjects. Here, we used immunocytochemical methods to examine the association of these acute-phase proteins with the characteristic diffuse plaques of cerebellum in AD. We observed AP and complement C3d, C1q, C5 and C4bp immunoreactivities in most Aβ-protein-reactive plaques of the cerebellum. Further, a 1-antichymotrypsin immunoreactivity was apparent in at least 60% of all the cerebellar diffuse plaques examined. Cerebellar tissue bearing the Aβ-protein deposits also often exhibited marked angiopathy in the pial vessels. We suggest that diffuse plaques of the cerebellum also acquire components of the chronic inflammatory response evident in neocortical plaques.

Isolated atrial amyloidosis: A clinicopathologic study indicating increased prevalence in chronic heart disease

Congo red screening of 211 consecutive cardiac biopsy specimens obtained during cardiac surgery from 167 patients revealed 26 (16%) instances of isolated atrial amyloidosis (IAA). The ages of IAA-positive patients ranged from 25 to 52 years (mean age, 39 years). Twenty-three (88%) IAA-positive biopsy specimens were from patients with chronic rheumatic heart disease (CRHD) while three (12%) were from patients with an atrial septal defect (ASD). The prevalence of IAA in the CRHD patients was 23%, appreciably higher than that in the ASD patients (15%) and in other patients with atrial biopsies. The prevalence of IAA in both CRHD and ASD patients was significantly higher ( P < .001) than in controls. Controls consisted of 247 healthy adults who were autopsied after traumatic deaths, with an age range of 18 to 89 years (mean age, 38 years). Only seven (3%) control subjects were IAA positive; all were over 40 years of age. Isolated atrial amyloidosis deposits were permanganate resistant and immunohistochemically positive for human amyloid P (AP) protein and negative for human amyloid-associated (AA) protein and immunoglobulin light chains. They were observed as fine congophilic and birefringent deposits in intramyocardial vessel walls, along the myocardial sarcolemma, and in the subendocardium. There was associated myocyte hypertrophy but no atrophy. Electron microscopy demonstrated typical nonbranching amyloid fibrils. It is postulated that stretching of the atria in chronic heart disease results in a raised prevalence of IAA. Recent reports that IAA contains atrial natriuretic peptide, a polypeptide hormone product of atrial myocytes, supports this view.

Serum Amyloid P Component: A Predictor of Clinical β2-Microglobulin Amyloidosis

Beta 2-microglobulin (beta 2M) amyloidosis is common in patients on long-term hemodialysis, but the clinical conditions associated with disease activity are poorly understood. This study was designed to determine if the serum amyloid P (AP) component concentration is predictive of beta 2M amyloid disease activity. Serum AP component concentrations were determined by rocket immunoelectrophoresis and beta 2M concentrations by a commercially available kit. Radiographic evidence of beta 2M amyloidosis was determined from bone films of the hips, shoulders, and hands. Serum AP component concentrations were not different in dialysis and control patients. However, AP component concentrations in long-term (greater than or equal to 5 years) dialysis patients were significantly lower than in short-term (less than 5 years) dialysis patients (43.0 +/- 16.9 micrograms/mL [n = 28] v 56.0 +/- 18.3 micrograms/mL [n = 31], P less than 0.05). The patients on hemodialysis for 5 or more years who had radiographic evidence of severe beta 2 M amyloidosis were significantly older (57.9 +/- 9.5 v 38.3 +/- 11.3 years, P less than 0.001) and their serum AP concentrations were significantly lower (34.3 +/- 15.0 v 50.1 +/- 15.6 micrograms/mL, P less than 0.05) than long-term dialysis patients without radiographic evidence of disease. Stepwise regression analysis showed that the patient's age and serum AP component concentration were predictors of radiographic evidence of beta 2 M amyloidosis. Thus, serum AP component concentrations are decreased in long-term dialysis patients, suggesting accelerated deposition into amyloid deposits.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum Amyloid P in Alzheimer's Disease

We describe widespread serum amyloid P (AP) immunoreactivity in cerebral lesions including neurofibrillary tangles, senile plaques, and vessels in Alzheimer's disease (AD). To elucidate the mechanisms of its origin in cerebrospinal fluid and localization in brain, we searched for AP mRNA by the polymerase chain reaction. Our findings show that with the exception of liver, AP mRNA was not detectable in any of the brain regions tested or choroid plexus. These observations support extravasation or transport of this serum protein across the blood-brain barrier or the blood-cerebrospinal fluid barrier in the brain of subjects with AD.

Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer's disease and other degenerative disorders

Amyloid P (AP) component is present in all types of systemic amyloid deposits. Recently, it has been shown to be also present in cerebral amyloid lesions of Alzheimer's disease (AD). In this study, we used immunocytochemical methods to extend these findings at the electron microscope level and characterize the spectrum of AP immunoreactivity in neurofibrillary pathology (NFP) of AD and other neurodegenerative disorders including Down's syndrome (DS), Creutzfeldt-Jakob, Parkinson's, Pick's and diffuse Lewy body diseases and progressive supranuclear palsy. In AD and DS, AP immunoreaction product was evident in all the classical amyloid lesions and NFP in a large sample of all cortical areas examined. The distribution and relative intensity of immunostaining was similar to that of thioflavin S staining in serial sections. In many cases, however, plaques and vessels stained by anti-AP serum were not apparent with thioflavin S. Serial sections immunostained with antiserum to amyloid A, C-reactive protein or to other proteins involved in systemic amyloidoses and the acute phase response showed no evidence of staining in any of the cerebral lesions. Electron microscopy confirmed that AP immunoreactivity was associated with the abnormal filaments characteristic of NFP as well as amyloid fibrils found in plaques and vessels showing congophilic amyloid angiopathy. Plaques of Creutzfeldt-Jakob disease, Pick bodies of Pick's disease, tangles and Lewy bodies in Parkinson's disease and a subpopulation of Lewy bodies in the diffuse Lewy body disease coexistent with AD were also stained. With the exception of vessels in two of the five cases, AP was not detected in age-matched controls. Our observations indicate AP to be a consistent feature of cerebral NFP and amyloid deposits.

Immunohistochemical identification of the AA protein in lattice dystrophy

We examined the amyloid deposits of lattice dystrophy type I for common components of primary and secondary amyloid using the sensitive unlabelled antibody peroxidase-antiperoxidase technique. Tissue sections of formalin-fixed, paraffin-embedded specimens from three patients with lattice dystrophy were reacted with antisera specific for free immunoglobulin light chains, prealbumin, amyloid A (AA) protein, and amyloid P (AP) protein. The lattice amyloid was positive for the AA protein associated with secondary amyloid. The deposits were also stained with the protein AP antiserum in each case. We were unable to detect the presence of immunoglobulin light chains associated with primary amyloid or prealbumin associated with another heredofamilial form of amyloid. Sera from two patients with lattice dystrophy were tested for the presence of the serum amyloid A related protein, the apparent precursor of AA amyloid, by immunoelectrophoresis and immunodiffusion. The sera showed no reaction with the AA antiserum with these techniques. Lattice amyloid differed from secondary systemic amyloid in the reaction with potassium permanganate. Congo red staining of lattice deposits was not abolished by treatment with potassium permanganate. Our findings suggest that the amyloid proteins in lattice dystrophy are antigenically similar to those of secondary amyloid and the hereditary form associated with familial Mediterranean fever.

Homologs of CRP: a diverse family of proteins with similar structure.

Human C-reactive protein (CRP) was first noted over 50 years ago (Tillet and Francis, 1930) as a serum protein that rapidly increased in concentration in diseased patients. Inflammation or injury will nonspecifically cause a variety of serum constituents to fluctuate from normal levels; these proteins are designated acute phase reactants (Owen, 1967). However, human CRP is regarded as the archetype acute phase protein because of its relatively long history and impressive serum changes as an acute reactant. Since the discovery of CRP, numerous investigators have puzzled over its function in inflammation. Another protein, a constituent of human amyloid called amyloid P (AP) component, has been shown to be homologous to CRP (Osmand et al., 1977a; Levo et al., 1977). Because these proteins have been the subject of several excellent current reviews (Koj, 1974; Kushner, 1981; Gewurz et al., 1982;Pepys, 1981;Kushner et al., 1982), this chapter will deal primarily with the expression of proteins homologous with human CRP and AP that have been identified in other animals. In general, these two proteins are represented in a wide variety of species, from fishes to mammals, and a conservative evolution has resulted in functional characteristics similar to those of their human counterparts. These proteins also have a similar unique structure.