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Synaptic dysfunction and oxidative stress in Alzheimer’s disease: Emerging mechanisms

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      Abstract

      In this paper, we review experimental advances in molecular neurobiology of Alzheimer’s disease (AD), with special emphasis on analysis of neural function of proteins involved in AD pathogenesis, their relation with several signaling pathways and with oxidative stress in neurons. Molecular genetic studies have found that mutations in APP, PS1 and PS2 genes and polymorphisms in APOE gene are implicated in AD pathogenesis. Recent studies show that these proteins, in addition to its role in beta-amyloid processing, are involved in several neuroplasticity-signaling pathways (NMDA-PKA-CREB-BDNF, reelin, wingless, notch, among others). Genomic and proteomic studies show early synaptic protein alterations in AD brains and animal models. DNA damage caused by oxidative stress is not completely repaired in neurons and is accumulated in the genes of synaptic proteins. Several functional SNPs in synaptic genes may be interesting candidates to explore in AD as genetic correlates of this synaptopathy in a “synaptogenomics” approach. Thus, experimental evidence shows that proteins implicated in AD pathogenesis have differential roles in several signaling pathways related to neuromodulation and neurotransmission in adult and developing brain. Genomic and proteomic studies support these results. We suggest that oxidative stress effects on DNA and inherited variations in synaptic genes may explain in part the synaptic dysfunction seen in AD.

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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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        Alzheimer's disease is a synaptic failure.

         D. Selkoe (2002)
        In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.
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          Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

          A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.
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            Author and article information

            Affiliations
            [a ]Grupo de Neurociencias, Facultad de Medicina e Instituto de Genética, Universidad Nacional de Colombia Bogotá, Colombia
            [b ]Institute of Pathology, Case Western Reserve University Cleveland, OH, USA
            [c ]Departamento de Pediatria, Facultad de Medicina, Universidad Nacional de Colombia Bogotá, Colombia
            [4 ]Current Affiliation: Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, University of Antwerp Antwerp, Belgium
            Author notes
            *Correspondence to: Dr. Humbgerto ARBOLEDA Instituto de Genética, Universidad Nacional de Colombia, Ciudad Universitaria, Bogotá, Colombia, Ciudad Universitaria, Bogotá, Colombia. Tel.: +57-1-3165000, ext. 11613 Fax: +57-1-3165526 E-mail: harboledag@ 123456unal.edu.co
            Journal
            J Cell Mol Med
            J. Cell. Mol. Med
            jcmm
            Journal of Cellular and Molecular Medicine
            John Wiley & Sons, Ltd (Chichester, UK )
            1582-1838
            1582-4934
            July 2006
            01 May 2007
            : 10
            : 3
            : 796-805
            16989739 3933161 10.1111/j.1582-4934.2006.tb00439.x
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