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      Transthyretin Amyloidosis: Chaperone Concentration Changes and Increased Proteolysis in the Pathway to Disease

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          Transthyretin amyloidosis is a conformational pathology characterized by the extracellular formation of amyloid deposits and the progressive impairment of the peripheral nervous system. Point mutations in this tetrameric plasma protein decrease its stability and are linked to disease onset and progression. Since non-mutated transthyretin also forms amyloid in systemic senile amyloidosis and some mutation bearers are asymptomatic throughout their lives, non-genetic factors must also be involved in transthyretin amyloidosis. We discovered, using a differential proteomics approach, that extracellular chaperones such as fibrinogen, clusterin, haptoglobin, alpha-1-anti-trypsin and 2-macroglobulin are overrepresented in transthyretin amyloidosis. Our data shows that a complex network of extracellular chaperones are over represented in human plasma and we speculate that they act synergistically to cope with amyloid prone proteins. Proteostasis may thus be as important as point mutations in transthyretin amyloidosis.

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          Most cited references 54

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          A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves.

           Luis Andrade (1952)
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            Fibrinogen is associated with an increased risk of Alzheimer disease and vascular dementia.

            Vascular and inflammatory factors may play an important role in the pathogenesis of dementia. Studies reported an association between plasma levels of inflammation markers and the risk of dementia. Both fibrinogen and C-reactive protein are considered inflammatory markers. Fibrinogen also has important hemostatic properties. We investigated the association of fibrinogen and C-reactive protein with dementia. The study was based on the prospective population-based Rotterdam Study. Fibrinogen was measured in a random sample of 2835 persons. High-sensitivity C-reactive protein was measured in the total cohort of 6713 persons. We identified 395 incident dementia cases during follow-up (mean, 5.7 years). We estimated the associations of fibrinogen and C-reactive protein with dementia using Cox proportional hazard models. Persons with higher levels of fibrinogen had an increased risk of dementia. The hazard ratio for dementia per SD increase of fibrinogen was 1.26 (95% CI, 1.11 to 1.44), adjusted for age and gender, and 1.30 (95% CI, 1.13 to 1.50) after additional adjustment for cardiovascular factors and stroke. For Alzheimer disease, the adjusted hazard ratio was 1.25 (95% CI, 1.04 to 1.49), and for vascular dementia it was 1.76 (95% CI, 1.34 to 2.30). High levels of C-reactive protein were not associated with an increased risk of dementia. High fibrinogen levels were associated with an increased risk of both Alzheimer disease and vascular dementia, but levels of C-reactive protein were not. This suggests that the increased risk of dementia associated with fibrinogen is because of the hemostatic rather than the inflammatory properties of fibrinogen.
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              Dynamics of gene expression for a hippocampal glycoprotein elevated in Alzheimer's disease and in response to experimental lesions in rat.

              A hippocampal poly(A) RNA, pADHC-9, was cloned by differential screening of a human hippocampal cDNA library. By RNA blot analysis, pADHC-9 was elevated 2-fold in Alzheimer's disease hippocampus. In situ analyses identified pADHC-9 expression in pyramidal and non-pyramidal cells of the hippocampus and entorhinal cortex. Nucleotide sequence analysis identified pADHC-9 as a potential human homolog of rat sulfated glycoprotein 2 (SGP-2). SGP-2 expression increased in rat hippocampus following experimental lesions that mimic intrinsic neuronal loss and/or deafferentation. The function of pADHC-9 in brain has not been defined, but in serum, a similar protein inhibits complement-dependent cytolysis. Increased expression of pADHC-9 in Alzheimer's disease hippocampus may be a compensatory response mounted to retard a complement-driven neurodegenerative cascade.

                Author and article information

                Role: Editor
                PLoS One
                PLoS ONE
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                6 July 2015
                : 10
                : 7
                [1 ]Centro de Química e Bioquímica, FCUL, Campo Grande, Lisboa, Portugal
                [2 ]Instituto de Tecnologia Química e Biológica, Av. da República Estação Agronómica Nacional, Oeiras, Portugal
                [3 ]Unidade de Transplantação, Hospital Curry Cabral, Lisboa, Portugal
                Aligarh Muslim University, INDIA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: GC APF CC. Performed the experiments: GC CRS RR SG RAG. Analyzed the data: AF RAG. Contributed reagents/materials/analysis tools: AVC EM EB. Wrote the paper: GC CC.


                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                Page count
                Figures: 3, Tables: 1, Pages: 17
                Work was supported by grants SFRH/BPD/41037/2007 (R.A.G.) and SFRH/BPD/73779/2010 and IF/00359/2014 (G.C), PEst-OE/QUI/UI0612/2011, PTDC/QUI/123060/2010 and REDE/1501/REM/2005 from the Fundação para a Ciência e a Tecnologia, and also by the 2011 Junior Research grant from the amyloidosis foundation.
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