Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis
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We report the in vivo evaluation, in a murine model, of MRI measurements of the extracellular volume fraction (ECV) for the detection and monitoring of systemic amyloidosis. A new inducible transgenic model was used, with increased production of mouse serum amyloid A protein controlled by oral administration of doxycycline, that causes both the usual hepatic and splenic amyloidosis and also cardiac deposits. ⋯ In a further four mice that received human serum amyloid P component (SAP) followed by anti-human SAP antibody, a treatment to eliminate visceral amyloid deposits, ECV in the liver and spleen returned to baseline after therapy (p < 0.01). MRI measurement of ECV is a sensitive marker of amyloid deposits with potential application for early detection and monitoring therapies promoting their clearance.
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Comparative Study
Loss of gastric interstitial cells of Cajal in patients with hereditary transthyretin amyloidosis.
Hereditary transthyretin (TTR) amyloidosis is a systemic neuropathic disorder caused by TTR gene mutations. Gastrointestinal complications are common and the underlying mechanisms remain unclear. The interstitial cells of Cajal (ICC) function as pacemaker cells in the gastrointestinal tract and are important for gastrointestinal motility. The aim of this study was to investigate the densities of gastric ICC and nerves in patients with TTR amyloidosis compared to non-amyloidosis controls. ⋯ A loss of gastrointestinal ICC may be an important factor for the digestive disturbances in hereditary TTR amyloidosis.
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Quantitation of peripheral amyloid deposits by non-invasive molecular imaging can be useful for diagnosis, prognostication and monitoring response to therapy. In order to obtain reliable quantitative data, it is necessary to show a linear positive correlation between the uptake of the molecular probe and the tissue amyloid load. The transgenic H-2/IL-6 mouse model of AA amyloidosis was used to generate animals with varied stages of visceral amyloid disease. ⋯ Furthermore, biodistribution studies revealed that the amount of 125I deposited in liver and spleen correlated with the amount of CR birefringence (expressed as 0-4+ or as tissue area [µm2]) in these tissues with correlation coefficients of r > 0.7 (p < 10(-6)). Deposition of 125I-p5 is a quantitative measure of the amount of AA amyloid in liver and spleen in this mouse model. The p5 peptide has potential as a quantitative amyloid imaging agent in human disease.
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The polyphenol, 1,2,3,4,6-penta-O-galloyl-β-D-glucose (PGG) has been found to exhibit a host of positive pharmacologic activities, including anti-cancer and anti-diabetic. Little is known about the mode of action of PGG in yielding these positive activities. We show here that PGG is a potent inhibitor of IAPP (islet amyloid polypeptide, amylin) aggregation. ⋯ PGG was compared to the known amyloid inhibitors (and structural relatives); tannic acid and gallic acid. In every test, PGG was far superior to tannic and gallic acids at inhibiting amyloid aggregation. These results indicate that PGG is a potent inhibitor of IAPP amyloid aggregation and a potential lead molecule for development of an amyloid inhibiting therapeutic.
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Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by accumulation of amyloid plaques and neurofibrillary tangles. Amyloid-β (Aβ) is widely recognized as a key factor in the pathogenesis of AD. Aβ1-42 a major component of amyloid plaques, has shown synaptotoxicity associated with impaired long-term potentiation and cognitive deficits. ⋯ We also found that the Aβ1-42-mediated decline of neurogenesis was associated with decreased protein levels of cytokines interferon-γ (IFN-γ) and transcription factor nuclear factor-kappa B (NF-κB) in the hippocampus. These results suggest that Aβ1-42 inhibits hippocampal neurogenesis in the adult brain possibly through down-regulation of INF-γ and NF-κB signaling pathway. This study provides a new insight into Aβ1-42-mediated decrease in hippocampal neurogenesis in the adult central nervous system.