PRESENTED BY

S.MOHAMMED RAZEETH

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

The principal neuropathological features of

AD

neurofibrillary tangleS

β-amyloid (Aβ)

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

MICROTUBULE

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.

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

Three classes of ptn involve in transport

The myosins-for the microfilament tracks

The kinesins and dyneins -for microtubule

tracks

NURONS SIGNALING

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.

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.

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

TAU

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).

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)

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

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

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

MUTATION

There are three types of mutation reported in

Tau protien

20 missense mutation

3 silent mutation

2 deletion mutation

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.

TAU AGGREGATION

Tau important for its abnormal behavior in AD

is the aggregation into fibers

Excellent solubility

which counteracts aggregation in

physiological buffers.

Any doubts?

Thank you