Alzheimer’s disease

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Text of Alzheimer’s disease

Presented by s.mohammed razeeth

Presented bys.mohammed razeeth

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

The principal neuropathological features of AD

neurofibrillary tangleS

-amyloid (A)

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 systemmicrotubule

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 cellTraffic systems in the form of cytoskeletal fibers which guide the transport of motor proteinsTwo distinct fiber systems for transport

The actin microfilaments and The microtubulesThree classes of ptn involve in transport

The myosins-for the microfilament tracks

The kinesins and dyneins -for microtubule tracksNurons signaling

Functions of tau protienIntracellular 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.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

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 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)

PHOSPHORLATION SITESThese phosphorylation sites can be sub-divided into 2 groups

Residues that are phosphorylated by prolinedirected kinases

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)

which can be phosphorylated by Tyr-directed kinases e.g.Y18 by the kinase fyn, Bhaskar et al., 2005

MUTATIONThere are three types of mutation reported in Tau protien

20 missense mutation3 silent mutation 2 deletion mutation

Effect of mutationMutation 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 aggregationTau important for its abnormal behavior in AD is the aggregation into fibersExcellent solubilitywhich counteracts aggregation in physiological buffers.

Any doubts? Thank you

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