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[From A Report on Alzheimer's Disease and Current Research by Dr. Jack Diamond, scientific director of the Alzheimer Society of Canada]
Four brain changes that occur with Alzheimer's disease
The major unknown in Alzheimer research is exactly how
the risk factors lead to the development of oxidative stress
in the brain and to the production of the characteristic
pathological changes, of which the most prominent are the
loss of nerve cells, the appearance of plaques and tangles, and
inflammation. Once these are produced, however, their threat
to the brain is beginning to be well understood, leading to
the rational design of drugs and the promotion of a healthy
lifestyle, all with the aim of reducing that threat.
i. The plaques
These are made largely of the protein already
mentioned, called beta amyloid, or A-beta, which is
actually split off from a much larger protein molecule
known as APP. Both APP and A-beta are present
in normal brains, but their function is still under
investigation. The key problem in Alzheimer's disease
is that abnormally high amounts of A-beta accumulate
in the brain, overwhelming the enzymes and other
molecules whose job it is to clear it away. As well, the
clearing away process itself appears to be defective.
This applies even in the aging brain, in which at least
two of the enzymes that help eliminate A-beta become
progressively reduced whether Alzheimer's disease
is present or not. It is now accepted that the real
danger comes when the individual A-beta molecules
clump together to form small toxic aggregates called
oligomers. The continuing aggregation eventually leads
to the formation of the amyloid plaques. However,
the oligomers are so toxic that by the time the plaques
appear the damage seen in the Alzheimer brain has
already occurred.
The "neurofibrillary tangles", to give them their full
name, are made of a protein called tau, which, like
amyloid, occurs in normal nerve cells, but in Alzheimer's
disease it becomes chemically altered and piles up
as thread-like tangles, impairing tau's key roles in
nerve cells. One of these roles is in nerve sprouting,
an important feature of self-repair in the nervous
system which is described later. Another tau role is in
maintaining a kind of railway track system inside nerve
cells that moves needed chemicals and tiny organelles
up and down the nerve fibres between the cell body and
the distant nerve endings. The cell body is the factory
and powerhouse for the entire nerve cell. This transport
system is essential for the cell to work and survive, and
the tangles disrupt it and in a sense choke the cells to
death. The first casualties of disrupted transport are the
nerve endings, which contact the next cells in the circuit;
these junctions are called synapses. They're vulnerable
because they're so far away from their cell bodies, the
source of their nutrients. Consequently the earliest signs
of disturbed nerve cell function are seen at the synapses,
and in animal models of Alzheimer's disease it is here
that researchers focus to see if future therapies are
proving successful.
A controversy
Many researchers believe that the amyloid deposits
not only make the nerve cells sick, but they somehow
promote the development of tangles, and it is probably
these that actually kill the nerve cells. In keeping with
this "cascade hypothesis", when mice models of
Alzheimer's disease were immunized against A-beta, not
only the plaques but the tangles tended to disappear.
Moreover tangles generally appear after the plaques
have developed. In any event both plaques and tangles
are definitely implicated in Alzheimer's disease. New
research is suggesting that a very early event is the entry
of the accumulating A-beta molecules into the nerve
cells where the A-beta interacts with tau molecules that
may be already altered, to form a deadly toxic product
that is responsible for the earliest degenerative changes
in the nerve cells and synapses.
But the situation is complicated. The brains of some
normal elderly people have been found to have as many
amyloid plaques as in Alzheimer brains, but there was
no dementia! Nevertheless, most researchers still regard
A-beta as the main threat, and still direct their efforts to
eliminating it. This laudable and necessary attempt to
cure the disease may not, however, be enough. To cure
the person with the disease needs more, as will be seen
later!
iii. Inflammation of the brain
Whenever and wherever the body suffers trauma, or
is attacked by some kind of potentially threatening
influence such as an infection or a toxin, it defends
itself in part by mounting an "inflammatory response".
This, which is actually an immune response, also
occurs in the Alzheimer brain. Unfortunately the
disease challenge is so great that the response becomes
excessive, and instead of helping it actually worsens
the situation. When the brain's immune cells (called
microglia) become overactive they seem to overproduce
substances that are normally protective, to a level which
actually promotes death of cells. Moreover new results
are suggesting that in Alzheimer's disease the very early activation of these microglia actually helps trigger the
changes in the tau protein that result in the formation
of tangles.
iv. Shrinkage and degeneration of nerve cells
As nerve cells die and disappear that part of the brain
shrinks. This process, which first begins in the part
of the brain that deals with thinking and memory, is
progressive, eventually affecting all parts of the brain,
which consequently shrinks as a whole. The shrinkage
is most marked, however, in the thinking and memory
regions, and this is very readily seen by brain imaging.
Dr. Alzheimer noted and described three of the above
pathological changes seen in the Alzheimer brain (i,
ii, and iv). It's understandable that he missed number
(iii), inflammation, since the recognition of immune
cells in the brain and their functions had not yet
entered medical science, nor had the concept and the
importance of oxidative stress.
[The contents of this page are provided for information purposes only and do not represent advice, an endorsement or a recommendation, with respect to any product, service or enterprise, and/or the claims and properties thereof, by the Alzheimer Society of Canada. The information contained in this report was current at the time of printing, April 2008.]
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