Presented by s.mohammed razeeth

1. Presented bys.mohammedrazeeth

2. Alzheimer’s disease (AD), the most common form of age-related dementia neurodegeneration of the central nervous system That eventually leads to a gradual decline of cognitive function and dementia INTRODUCTION

3. The principal neuropathological features of AD neurofibrillarytangleS β-amyloid (Aβ)

5. Tau protien Tau is a low molecular weight microtubule associated protein (MAP) In human tau found in neurons of both the peripheral and central nervous system neurofibrillarytangleS

6. microtubule

7. very low levels of tau expression have also been reported in glial cells Find out by Binder et al., 1985; Cleveland et al., 1977; Couchie et al., 1992; LoPresti et al., 1995; Shin et al., 1991.

8. Traffic systems in the form of cytoskeletal fibers which guide the transport of motor proteins Two distinct fiber systems for transport The actin microfilaments and The microtubules Traffic system of the cell

9. Three classes of ptn involve in transport The myosins-for the microfilament tracks The kinesins and dyneins -for microtubule tracks

10. Nurons signaling

11. Intracellular vesicular transport Organization of the actin cytoskeleton Anchoring of phosphatases and kinases By Buee et al., 2000;Lee et al., 2001. Functions of tau protien

12. Tau is best characterized for its ability to bind to stabilize and promote the polymerization of microtubules In Human tau encode single gene located on chromosome 17q21-22 that consists of 16 exons.

13. Isoforms generated by alternative mRNA splicing By Andreadis et al., 1992; Neve et al in1986 Alternative splicing of exons (E) 2 (E2), 3(E3) and 10 (E10) It produce 6 isoforms ranging in length from 352 to 441 amino acids isoforms

14. tau

15. It has 3R and 4R carboxy-terminal repeats Along with specifically identified adjacent sequences are responsible for the binding of tau to MT (Butner and Kirschner, 1991; Gustke et al., 1994; Lee et al., 1989).

16. Tau is a phosphoprotein with 79 potential serine or threonine It has (Ser/Thr) phosphorylation acceptor sites Tau phosphorylation is a normal physiological process Which decreases tau’s binding affinity for MTs (Biernat et al., 1993; Bramblett et al., 1993; Drechsel et al., 1992; Yoshida and Ihara, 1993)

18. These phosphorylation sites can be sub-divided into 2 groups Residues that are phosphorylated by prolinedirectedkinases Residues that arephosphorylated by non-prolinedirectedkinases PHOSPHORLATION SITES

19. Early stages of degeneration can be detected by means of phosphorylation-sensitive antibodies Sites occur in SP or TP motifs (7 and 10,resp.) which are preferred targets of proline-directed kinases examples: MAPkinase, GSK-3β

20. tau contains 5 tyrosines (no. 18, 29, 197,310, 394) which can be phosphorylated by Tyr-directed kinases e.g.Y18 by the kinasefyn, Bhaskar et al., 2005

22. There are three types of mutation reported in Tau protien 20 missense mutation 3 silent mutation 2 deletion mutation MUTATION

24. Mutation in tau promotes tau dysfunction and it turn leads to intracellular aggregates There are two main pathogenic mechanisms (i) altering the mRNA splicing of exon 10 (ii) decreasing tau-MT interactions. Effect of mutation

25. Tau important for its abnormal behavior in AD is the aggregation into fibers Excellent solubility which counteracts aggregation in physiological buffers. Tau aggregation

27. Any doubts?

28. Thank you