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      Protein aggregation and neurodegenerative disease

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      Nature Medicine
      Springer Science and Business Media LLC

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          Abstract

          Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and prion diseases are increasingly being realized to have common cellular and molecular mechanisms including protein aggregation and inclusion body formation. The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid. There is partial but not perfect overlap among the cells in which abnormal proteins are deposited and the cells that degenerate. The most likely explanation is that inclusions and other visible protein aggregates represent an end stage of a molecular cascade of several steps, and that earlier steps in the cascade may be more directly tied to pathogenesis than the inclusions themselves. For several diseases, genetic variants assist in explaining the pathogenesis of the more common sporadic forms and developing mouse and other models. There is now increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity. These are leading to approaches toward rational therapeutics.

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          Most cited references122

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          The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.

          It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid beta-peptide (Abeta) in plaques in brain tissue. According to the amyloid hypothesis, accumulation of Abeta in the brain is the primary influence driving AD pathogenesis. The rest of the disease process, including formation of neurofibrillary tangles containing tau protein, is proposed to result from an imbalance between Abeta production and Abeta clearance.
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            Alpha-synuclein in Lewy bodies.

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              Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

              Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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                Author and article information

                Journal
                Nature Medicine
                Nat Med
                Springer Science and Business Media LLC
                1078-8956
                1546-170X
                July 2004
                July 1 2004
                July 2004
                : 10
                : S7
                : S10-S17
                Article
                10.1038/nm1066
                15272267
                773737f3-a7da-4f47-baaf-05244dbd7e97
                © 2004

                http://www.springer.com/tdm

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