Alzheimer’s disease

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<p>Presented by s.mohammed razeeth</p> <p>Presented bys.mohammed razeeth</p> <p>INTRODUCTIONAlzheimers disease (AD), the most common form of age-related dementianeurodegeneration of the central nervous system That eventually leads to a gradual decline of cognitive function and dementia</p> <p>The principal neuropathological features of AD</p> <p>neurofibrillary tangleS</p> <p>-amyloid (A)</p> <p>neurofibrillary tangleS</p> <p>Tau protien</p> <p>Tau is a low molecular weight microtubule associated protein (MAP)</p> <p>In human tau found in neurons of both the peripheral and central nervous systemmicrotubule</p> <p>very low levels of tau expression have also been reported in glial cells</p> <p>Find out by Binder et al., 1985; Cleveland et al., 1977; Couchie et al., 1992; LoPresti et al., 1995; Shin et al., 1991.Traffic system of the cellTraffic systems in the form of cytoskeletal fibers which guide the transport of motor proteinsTwo distinct fiber systems for transport</p> <p> The actin microfilaments and The microtubulesThree classes of ptn involve in transport</p> <p>The myosins-for the microfilament tracks</p> <p>The kinesins and dyneins -for microtubule tracksNurons signaling</p> <p>Functions of tau protienIntracellular vesicular transport</p> <p> Organization of the actin cytoskeleton</p> <p>Anchoring of phosphatases and kinases</p> <p>By Buee et al., 2000;Lee et al., 2001.Tau is best characterized for its ability to bind to stabilize and promote the polymerization of microtubules</p> <p>In Human tau encode single gene located on chromosome 17q21-22 that consists of 16 exons.isoformsIsoforms generated by alternative mRNA splicing By Andreadis et al., 1992; Neve et al in1986Alternative splicing of exons (E) 2 (E2), 3(E3) and 10 (E10)It produce 6 isoforms ranging in length from 352 to 441 amino acidstau</p> <p>It has 3R and 4R carboxy-terminal repeats</p> <p>Along with specifically identified adjacent sequences are responsible for the binding of tau to MT </p> <p>(Butner and Kirschner, 1991; Gustke et al., 1994; Lee et al., 1989).Tau is a phosphoprotein with 79 potential serine or threonineIt has (Ser/Thr) phosphorylation acceptor sitesTau phosphorylation is a normal physiological processWhich decreases taus binding affinity for MTs(Biernat et al., 1993; Bramblett et al., 1993; Drechsel et al., 1992; Yoshida and Ihara, 1993)</p> <p> PHOSPHORLATION SITESThese phosphorylation sites can be sub-divided into 2 groups</p> <p>Residues that are phosphorylated by prolinedirected kinases</p> <p>Residues that are phosphorylated by non-prolinedirected kinasesEarly stages of degeneration can be detected by means of phosphorylation-sensitive antibodiesSites occur in SP or TP motifs (7 and 10,resp.) which are preferred targets of proline-directed kinases examples: MAPkinase, GSK-3tau contains 5 tyrosines (no. 18, 29, 197,310, 394)</p> <p>which can be phosphorylated by Tyr-directed kinases e.g.Y18 by the kinase fyn, Bhaskar et al., 2005</p> <p>MUTATIONThere are three types of mutation reported in Tau protien</p> <p>20 missense mutation3 silent mutation 2 deletion mutation</p> <p>Effect of mutationMutation in tau promotes tau dysfunction and it turn leads to intracellular aggregates</p> <p>There are two main pathogenic mechanisms</p> <p>(i) altering the mRNA splicing of exon 10(ii) decreasing tau-MT interactions.Tau aggregationTau important for its abnormal behavior in AD is the aggregation into fibersExcellent solubilitywhich counteracts aggregation in physiological buffers.</p> <p>Any doubts? Thank you</p>


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