Alzheimer’s disease
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Transcript of Alzheimer’s disease
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?