RECENT ADVANCES IN ALZHEIMERS RESEARCH

[Guest guest]

Dear all,

I would like to add information on Amyloid Precursor protein, and its conversion to amyloid

beta (Aß), in this nice ongoing discussion of Alzheimers’ Update series.

Data indicates that the deficit in APP in Alzheimers’s disease results from a decline in

production rather than an increase in catalysis.

Hereby, i am forwarding some links, for further reference.

Thanks

Points of consideration –

Amyloid Precursor Protein (APP)

Source - http://www.edinformatics.com/news/amyloid_precursor_protein.htm

1. It is an integral membrane protein expressed in many tissues and concentrated in the

synapses of neurons.

2. Primary function is not known, though it has been implicated as a regulator of synapse

formation and neural plasticity.

3. APP proteolysis is carried out firstly by beta secretase, that cuts off one end of

APP. Secondly, there is a role of gamma secretase – that carries out the final end product

formation - amyloid beta (Aß).

4. Both these secretases, could lead to future drug development. (Clinical trials have

been going on since 2007 taking these secretases as drug targets.)

5. APP is best known and most commonly studied as the precursor molecule whose

proteolysis generates amyloid beta (Aß), a 39- to 42-amino acid peptide whose amyloid

fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's

disease patients.

Genetics

1. The gene for APP is located on chromosome 21 and contains at least 18 exons in 240

kilobases.

2. Preferentially expressed in neuron..Homologous proteins have been identified in other

organisms such as Drosophila (fruit flies), C. elegans (roundworms), and all mammals. The

amyloid beta region of the protein, located in the membrane-spanning domain, is not well

conserved across species and has no obvious connection with APP's native-state biological

functions.

3. Mutations in critical regions of Amyloid Precursor Protein, including the region that

generates amyloid beta, are known to cause familial susceptibility to Alzheimer's disease.For

example, several mutations outside the Aß region associated with familial Alzheimer's have

been found to dramatically increase production of Aß.

Biological function

1. Role of APP is of obvious interest to Alzheimer's research, understanding has remained

elusive.

2. The most-substantiated role for APP is in synaptic formation and repair. Since its

expression is upregulated during neuronal differentiation and after neural injury.

3. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed

and supported by as-yet limited research.

4. The inference from animal studies is that because Aß accumulates excessively in

Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell

bodies contain less APP as a function of their proximity to amyloid plaques.

The data indicate that this deficit in APP results from a decline in production rather than an

increase in catalysis. Loss of a neuron's APP may effect physiological deficits that

contribute to dementia.

5. It is found that - Transport Protein ABCC1 Plays Key Role in Clearing Beta-Amyloid

from Brains of Mice

(ScienceDaily (Internet); Sep. 1, 2011 )

available at http://www.sciencedaily.com/releases/2011/09/110901134628.htm

a) Beta-amyloid accumulates in the brain of an individual with AD is that it is cleared

at a much reduced rate compared with that in the brain of an individual who is healthy.

The mechanistic reasons for this reduced beta-amyloid clearance are not well known.

c) But now, Pahnke and colleagues have determined that the transport protein ABCC1 has a

key role in clearing beta-amyloid from the brain of mice.

d) Of potential clinical interest, activation of ABCC1 using a drug approved by the FDA

to relieve nausea and vomiting (thiethylperazine) markedly reduced the amount of beta-amyloid

in the brains of mice with a condition that models AD.

e) So, authors suggest that pharmacological activation of ABC transporters could perhaps

impede the formation of amyloid plaques and thereby reduce the damage to the brain that

results in dementia in individuals with AD.

The research appears in the Journal of Clinical Investigation.

The AMYLOID CASCADE -

Amyloid cascade hypothesis and selected strategies for therapeutic intervention. The figure

summarizes the presumed sequence of pathological processes that leads to neurodegeneration in

AD according to the amyloid cascade hypothesis (Hardy and Selkoe, 2002), and indicates

selected potential approaches for therapeutic intervention.

link for amyloid cascade

http://brain.oxfordjournals.org/content/129/11/2840.full

REF - Hans-Wolfgang Klafki, Matthias Staufenbiel, Johannes Kornhuber, Jens Wiltfang.

Therapeutic approaches to Alzheimer's disease. Brain (2006); 129 (11): 2840-2855.Treat yourself at a restaurant, spa, resort and much more with Rediff Deal ho jaye!