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The Hallmarks of AD
Alzheimer’s disease disrupts critical metabolic processes that keep neurons
healthy. These disruptions cause nerve cells in the brain to stop working, lose
connections with other nerve cells, and finally die. The destruction and death
of nerve cells causes the memory failure, personality changes, problems in
carrying out daily activities, and other features of the disease.
The brains of people with AD have an abundance of two abnormal structures—amyloid
plaques and neurofibrillary
tangles—that are made of misfolded proteins (see "Protein
Misfolding" for more information). This is especially true in certain
regions of the brain that are important in memory.
The third main feature of AD is the loss of connections between cells. This
leads to diminished cell function and cell death.
AMYLOID PLAQUES
Amyloid plaques are found in the spaces between the brain’s nerve cells. They
were first described by Dr. Alois Alzheimer in 1906. Plaques consist of largely
insoluble deposits of an apparently toxic protein peptide, or fragment, called beta-amyloid.
We now know that some people develop some plaques in their brain tissue as
they age. However, the AD brain has many more plaques in particular brain
regions. We still do not know whether amyloid plaques themselves cause AD or
whether they are a by-product of the AD process. We do know that genetic
mutations can increase production of beta-amyloid and can cause rare, inherited
forms of AD (see "Genes
and Early-Onset Alzheimer’s Disease" for more on inherited AD).
To view a video showing what happens to the brain in AD, go to www.nia.nih.gov/Alzheimers/ADvideo.
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From APP to Beta-Amyloid Plaques
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Amyloid
precursor protein (APP), the starting point for
amyloid plaques, is one of many proteins associated with the cell
membrane, the barrier that encloses the cell. As it is being made inside
the cell, APP becomes embedded in the membrane, like a toothpick stuck
through the skin of an orange (Figure 1).
In a number of cell compartments, including the outermost cell
membrane, specific enzymes
snip, or cleave, APP into discrete fragments. In 1999 and 2000,
scientists identified the enzymes responsible for cleaving APP. These
enzymes are called alpha-secretase, beta-secretase, and gamma-secretase.
In a major breakthrough, scientists then discovered that, depending on
which enzyme is involved and the segment of APP where the cleaving
occurs, APP processing can follow one of two pathways that have very
different consequences for the cell.
In the benign pathway, alpha-secretase cleaves the APP molecule
within the portion that has the potential to become beta-amyloid. This
eliminates the production of the beta-amyloid peptide and the potential
for plaque buildup. The cleavage releases from the neuron a fragment
called sAPPα, which has beneficial properties, such as promoting
neuronal growth and survival. The remaining APP fragment, still tethered
in the neuron’s membrane, is then cleaved by gamma-secretase at the
end of the beta-amyloid segment. The smaller of the resulting fragments
also is released into the space outside the neuron, while the larger
fragment remains within the neuron and interacts with factors in the
nucleus (Figure 2).
In the harmful pathway, beta-secretase first cleaves the APP molecule
at one end of the beta-amyloid peptide, releasing sAPPβ from the
cell (Figure 3). Gamma-secretase then cuts the resulting APP fragment,
still tethered in the neuron’s membrane, at the other end of the beta-amyloid
peptide. Following the cleavages at each end, the beta-amyloid peptide
is released into the space outside the neuron and begins to stick to
other beta-amyloid peptides (Figure 4). These small, soluble aggregates
of two, three, four, or even up to a dozen beta-amyloid peptides are
called oligomers. Specific sizes of oligomers may be responsible for
reacting with receptors on neighboring cells and synapses, affecting
their ability to function.
It is likely that some oligomers are cleared from the brain. Those
that cannot be cleared clump together with more beta-amyloid peptides.
As the process continues, oligomers grow larger, becoming entities
called protofibrils and fibrils. Eventually, other proteins and cellular
material are added, and these increasingly insoluble entities combine to
become the well-known plaques that are characteristic of AD.
For many years, scientists thought that plaques might cause all of
the damage to neurons that is seen in AD. However, that concept has
evolved greatly in the past few years. Many scientists now think that
oligomers may be a major culprit. Many scientists also think that
plaques actually may be a late-stage attempt by the brain to get this
harmful beta-amyloid away from neurons.
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NEUROFIBRILLARY TANGLES
The second hallmark of AD, also described by Dr. Alzheimer, is neurofibrillary
tangles. Tangles are abnormal collections of twisted protein threads found
inside nerve cells. The chief component of tangles is a protein called tau.
Healthy neurons are internally supported in part by structures called microtubules,
which help transport nutrients and other cellular components, such as
neurotransmitter-containing vesicles,
from the cell body down the axon.
Tau, which usually has a certain number of phosphate molecules
attached to it, binds to microtubules and appears to stabilize them. In AD, an
abnormally large number of additional phosphate molecules attach to tau.
As a result of this “hyperphosphorylation,” tau disengages from the
microtubules and begins to come together with other tau threads. These tau
threads form structures called paired helical filaments, which can become
enmeshed with one another, forming tangles within the cell. The microtubules can
disintegrate in the process, collapsing the neuron’s internal transport
network. This collapse damages the ability of neurons to communicate with each
other.
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Loss of Connection Between
Cells
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(Click to Enlarge)
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| This illustration shows the damage caused by
AD: plaques, tangles, and the loss of connection between
neurons. |
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LOSS OF CONNECTION BETWEEN CELLS AND CELL DEATH
The third major feature of AD is the gradual loss of connections
between neurons. Neurons live to communicate with each other, and this vital
function takes place at the synapse. Since the 1980s, new knowledge about
plaques and tangles has provided important insights into their possible damage
to synapses and on the development of AD.
The AD process not only inhibits communication between neurons but can also
damage neurons to the point that they cannot function properly and eventually
die. As neurons die throughout the brain, affected regions begin to shrink in a
process called brain atrophy. By the final stage of AD, damage is widespread,
and brain tissue has shrunk significantly.
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