Tau is a microtubule-associated protein that stabilizes microtubules. In Alzheimer's disease, tau undergoes abnormal phosphorylation and forms neurofibrillary tangles in the brain. Tau has multiple isoforms and phosphorylation sites that regulate its ability to bind to microtubules. Mutations in tau can promote its dysfunction and aggregation into fibers, potentially contributing to neurodegeneration in Alzheimer's disease.

1. PRESENTED BY
S.MOHAMMED RAZEETH

2. INTRODUCTION
 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

3.  The principal neuropathological features of
AD
 neurofibrillary tangleS
 β-amyloid (Aβ)

5. NEUROFIBRILLARY TANGLES
 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

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 SYSTEM OF THE CELL
 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

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. FUNCTIONS OF TAU PROTIEN
 Intracellular vesicular transport
 Organization of the actin cytoskeleton
 Anchoring of phosphatases and kinases
 By Buee et al., 2000;Lee et al., 2001.

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
 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

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,

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

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 kinase fyn, Bhaskar et al.,
2005

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

24. EFFECT OF MUTATION
 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.

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

27. Any doubts?

28. Thank you