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The ubiquitin-proteasome system in Alzheimer's disease


Journal of Cellular and Molecular Medicine

Blackwell Publishing Ltd

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      Accumulation of proteins is a recurring event in many neurodegenerative diseases, including Alzheimer's disease (AD).Evidence has suggested that protein accumulation may result from a dysfunction in the ubiquitin proteasome system (UPS). Indeed, there is clear genetic and biochemical evidence of an involvement of the ubiquitin proteasome system in AD. This review summarizes the data supporting an involvement of the UPS in the pathogenesis of AD, focusing on the data showing the relationship between Aβ and tau, the two hallmark lesions of AD, and the UPS.

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

       D. Selkoe,  John Hardy (2002)
      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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        The ubiquitin system.

        The selective degradation of many short-lived proteins in eukaryotic cells is carried out by the ubiquitin system. In this pathway, proteins are targeted for degradation by covalent ligation to ubiquitin, a highly conserved small protein. Ubiquitin-mediated degradation of regulatory proteins plays important roles in the control of numerous processes, including cell-cycle progression, signal transduction, transcriptional regulation, receptor down-regulation, and endocytosis. The ubiquitin system has been implicated in the immune response, development, and programmed cell death. Abnormalities in ubiquitin-mediated processes have been shown to cause pathological conditions, including malignant transformation. In this review we discuss recent information on functions and mechanisms of the ubiquitin system. Since the selectivity of protein degradation is determined mainly at the stage of ligation to ubiquitin, special attention is focused on what we know, and would like to know, about the mode of action of ubiquitin-protein ligation systems and about signals in proteins recognized by these systems.
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          Global prevalence of dementia: a Delphi consensus study.

          100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region. 12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality. Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours. We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.

            Author and article information

            Department of Neurobiology and Behavior University of California, Irvine, CA, USA
            Author notes
            *Correspondence to: Salvatore ODDO, Department of Neurobiology and Behavior, University of California, Irvine, 1216 Gillespie Neuroscience, Irvine, CA 92697-4545, USA. Tel:+1 949 824 3471 Fax:+1 949 824 7356 E-mail: soddo@
            J Cell Mol Med
            J. Cell. Mol. Med
            Journal of Cellular and Molecular Medicine
            Blackwell Publishing Ltd (Oxford, UK )
            April 2008
            08 February 2008
            : 12
            : 2
            : 363-373
            18266959 3822529 10.1111/j.1582-4934.2008.00276.x
            ©2008 The Authors Journal compilation © 2008 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd

            Molecular medicine


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