Systemic Amyloid Disease Research Articles

High Hydrostatic Pressure Dissociates Early Aggregates of TTR 105–115, but not the Mature Amyloid Fibrils

A range of disorders such as Alzheimer's disease and type II diabetes have been linked to protein misfolding and aggregation. Transthyretin is an amyloidogenic protein which is involved in familial amyloid polyneuropathy, the most common form of systemic amyloid disease. A peptide fragment of this protein, TTR105-115, has been shown to form well-defined amyloid fibrils in vitro. In this study, the stability of amyloid fibrils towards high hydrostatic pressure has been investigated by Fourier transform infrared spectroscopy. Information on the morphology of the species exposed to high hydrostatic pressure was obtained by atomic force microscopy. The species formed early in the aggregation process were found to be dissociated by relatively low hydrostatic pressure (220 MPa), whereas mature fibrils are pressure insensitive up to 1.3 GPa. The pressure stability of the mature fibrils is consistent with a fibril structure in which there is an extensive hydrogen bond network in a tightly packed environment from which water is excluded. The fact that early aggregates can be dissociated by low pressure suggests, however, that hydrophobic and electrostatic interactions are the dominant factors stabilizing the species formed in the early stages of fibril formation.

Argpyrimidine, a methylglyoxal-derived advanced glycation end-product in familial amyloidotic polyneuropathy.

FAP (familial amyloidotic polyneuropathy) is a systemic amyloid disease characterized by the formation of extracellular deposits of transthyretin. More than 80 single point mutations are associated with amyloidogenic behaviour and the onset of this fatal disease. It is believed that mutant forms of transthyretin lead to a decreased stability of the tetramer, which dissociates into monomers that are prone to unfolding and aggregation, later forming beta-fibrils in amyloid deposits. This theory does not explain the formation of beta-fibrils nor why they are toxic to nearby cells. Age at disease onset may vary by decades for patients with the same mutation. Moreover, non-mutated transthyretin also forms the same deposits in SSA (senile systemic amyloidosis), suggesting that mutations may only accelerate this process, but are not the determinant factor in amyloid fibril formation and cell toxicity. We propose that glycation is involved in amyloidogenesis, since amyloid fibrils present several properties common to glycated proteins. It was shown recently that glycation causes the structural transition from the folded soluble form to beta-fibrils in serum albumin. We identified for the first time a methylglyoxal-derived advanced glycation end-product, argpyrimidine [N(delta)-(5-hydroxy-4,6-dimethylpyrimidin-2-yl)-L-ornithine] in amyloid fibrils from FAP patients. Unequivocal argpyrimidine identification was achieved chromatographically by amino acid analysis using dabsyl (4-dimethylaminoazobenzene-4'-sulphonyl) chloride. Argpyrimidine was found at a concentration of 162.40+/-9.05 pmol/mg of protein in FAP patients, and it was not detected in control subjects. The presence of argpyrimidine in amyloid deposits from FAP patients supports the view that protein glycation is an important factor in amyloid diseases.

Nodular Cutaneous Amyloid Tumors of the Eyelids in the Absence of Systemic Amyloidosis

A patient was referred with recurrent bilateral, slow-growing, painless, nodular tumors of the upper eyelid margins. The tumors were excised and the base of each lesion was ablated with the CO2 laser. Histological examination of the excised tissue revealed amyloid. Despite the fact that cutaneous, amyloid lesions of the eyelid have been previously described as essentially pathognomonic for systemic amyloid disease, no evidence of systemic amyloidosis was found in this patient. We believe that this represents only the second reported case of bilateral cutaneous amyloid of the eyelids without systemic involvement. We agree with previous authors that this lesion be added to the list of painless slow-growing bilateral eyelid tumors.

Soft-tissue amyloidoma

Amyloidoma of soft tissue is rare and there have been no previously published reports of limb involvement. We describe a case in which the tumour was present in the popliteal fossa. There was no evidence of systemic amyloid disease or of malignant neoplasm one year after the diagnosis.

Detection of distinct isoform patterns of the β-amyloid precursor protein in human platelets and lymphocytes

—Cerebral deposition of the amyloid β-protein (AβP), a ∼40 residue fragment of the integral membrane protein, β-amyloid precursor protein (βAPP), has been implicated as the probable cause of some cases of familial Alzheimer's disease (AD). The parallels between AβP deposition in AD and the deposition of certain plasma proteins in systemic amyloid diseases has heightened interest in the analysis of βAPP in circulating cells and plasma. Here, we describe distinct isoform patterns of βAPP in peripheral platelets and lymphocytes. PCR-mediated amplification of mRNA from purified platelets demonstrated the expression of all three major βAPP transcripts (βAPP 770,751,695). The full-length, ∼140 kDa form of βAPP 751,770 was detected in membranes of resting and activated platelets but very little immature, ∼122 kDa βAPP 751,770 was found, suggesting a different processing of βAPP in platelets than that described in a variety of cultured cells and tissues. Platelets stimulated with thrombin, calcium ionophore, or collagen released the soluble, carboxyl-truncated form of βAPP (protease nexin-II), but no evidence for the shedding of full-length βAPP associated with platelet microparticles was found, in contrast to previous reports. As a positive control marker for microparticles, the fibrinogen receptor subunit, GPIIIa, was readily detected in platelet releasates. Resting and activated platelets contained similar amounts of the ∼10 kDa carboxyl terminal βAPP fragment that is retained in platelet membranes following the constitutive cleavage of protease nexin-II. Nonstimulated peripheral B and T lymphocytes contained small amounts of membrane-associated mature and immature βAPP 751,770. The potentially amyloidogenic full-length βAPP molecules present in circulating platelets and lymphocytes but not in microparticles could serve as a source of the microvascular AβP deposited during aging and particularly in AD.

Lack of Amyloid in Abdominal Fat Aspirates From Patients Undergoing Long-term Hemodialysis

Recent reports describe the carpal tunnel syndrome (CTS) due to amyloid infiltration of the beta 2 microglobulin protein as a frequent complication of long-term hemodialysis. Carpal synovial and cystic bone lesion amyloid deposits have been reported; however, the extent of systemic amyloid deposition has not been determined. We examined 30 patients undergoing long-term hemodialysis for CTS and performed abdominal fat tissue aspiration for amyloid staining to evaluate the presence of systemic amyloid disease. In this group, CTS was frequent (37%) and its prevalence correlated with the duration of hemodialysis. In all patients, the abdominal fat tissue, stained with Congo red, was negative for amyloid deposits. These results confirm that CTS is a frequent complication of long-term hemodialysis; however, in this study, no detectable amyloid deposits were found in abdominal subcutaneous fat tissue. Thus, abdominal fat aspiration may not be a reliable screening test for hemodialysis-associated amyloidosis.

Lack of amyloid in abdominal fat aspirates from patients undergoing long-term hemodialysis

• Recent reports describe the carpal tunnel syndrome (CTS) due to amyloid infiltration of the β₂microglobulin protein as a frequent complication of long-term hemodialysis. Carpal synovial and cystic bone lesion amyloid deposits have been reported; however, the extent of systemic amyloid deposition has not been determined. We examined 30 patients undergoing long-term hemodialysis for CTS and performed abdominal fat tissue aspiration for amyloid staining to evaluate the presence of systemic amyloid disease. In this group, CTS was frequent (37%) and its prevalence correlated with the duration of hemodialysis. In all patients, the abdominal fat tissue, stained with Congo red, was negative for amyloid deposits. These results confirm that CTS is a frequent complication of long-term hemodialysis; however, in this study, no detectable amyloid deposits were found in abdominal subcutaneous fat tissue. Thus, abdominal fat aspiration may not be a reliable screening test for hemodialysis-associated amyloidosis. (<i>Arch Intern Med</i>1987;147:1455-1457)

Diagnosis of amyloidosis by abdominal fat aspiration. Analysis of four years' experience

Abdominal fat aspiration samples from 443 consecutive patients were examined for amyloid after Congo red and hematoxylin staining. Of the aspirates from 83 patients known to have systemic amyloid disease prior to the biopsy, 70 (84 percent) were found to yield positive results. The results for four aspirates from patients with localized amyloid disease were negative. Of the aspirates from 356 patients of unknown clinical status referred for analysis by outside physicians, 26 (7 percent) yielded positive results for amyloid. On review of the clinical records of these 26 patients, 11 had proved systemic amyloidosis demonstrated on biopsy of another site; all had a clinical course consistent with amyloid disease. In no case was amyloid found in a fat aspiration sample from a patient without clinical evidence suggestive of systemic amyloid disease. This study supports the proposal that abdominal fat aspiration is the diagnostic procedure of choice in the evaluation of amyloidosis since it requires no specialty consultation or technical expertise, causes minimal patient discomfort, and is accompanied by virtually no risk of morbid complication. A positive result has a high predictive value of amyloid disease in patients of unknown clinical status.

Ultrastructural features of cerebral amyloid angiopathy

Ultrastructural studies of the brain in three cases of cerebral amyloid angiopathy demonstrated that the vascular amyloid in this disease is composed of fibrils identical to those in systemic amyloid disease, mixed with a large amount of vesicular debris. Amyloid appears to be derived from circulating protein and is depostied in areas of vascular basement membrane degeneration. The initiating degenerative change is thickening of basement membrane with accumulation of debris. Inflammation, when present, tends to accelerate amyloid deposition locally. Amyloid transport from the vascular wall into the brain parenchyma proceeds by overflow when perivascular astroglial end-feet are disarranged. Structures of perivascular amyloid plaques are similar to the neuritic (senile) plaques in Alzheimer's disease, which were used as control, except that the amyloid core of the plaques in Alzheimer's disease is not related to blood vessels.

Conjunctival Amyloidosis in Association with Systemic Amyloid Disease: A case history

Conjunctival Amyloidosis in Association with Systemic Amyloid Disease: A case history

Oral manifestations of generalized systemic amyloid disease

A case of primary systemic amyloidosis is reported and the disease entity is discussed. The oral findings, including changes in the tongue and gingiva, are described. The importance of lingual and gingival biopsies is stressed.