because of their beta-pleated
sheets, these beta-amyloid monomers have a strong propensity to aggregate.
One beta-amyloid monomer can bind to another to form a beta-amyloid dimer,
or to several, to for a beta-amyloid oligomer. As aggregation
proceeds further, the beta-amyloid molecules form protofibrils,
measuring 3 to 6 nanometres (nm) in diameter and less than 100 nm in length,
and finally fibrils, measuring 10 nm in diameter and over
100 nm in length, which in turn aggregate into amyloid plaques.
experiments where insulin has been applied to hippocampal neurons, it has appeared
to protect them against damage from beta-amyloid oligomers, in particular by preventing
these molecules from binding to these neurons. And this protection can be augmented
by the administration of rosiglitazone, a medication for type 2 diabetes.
finding opens up the possibility of therapeutic strategies for Alzheimer’s
that might, for example, consist in making the patients’ neurons more sensitive
to the insulin produced naturally in their brains.
For this reason, research on the molecular mechanisms
of Alzheimer’s has begun to focus less on the non-soluble extracellular
deposits of beta-amyloid plaques and more on the soluble, non-fibrillar, oligomeric
form of beta-amyloid. In particular, researchers are looking at the role that
this form of beta-amyloid may play in synaptic pathology when produced in excessive
quantities (in lesser concentrations, it appears to plays a physiological role
that is not yet well understood).
beta-amyloid hypothesis is the name given to this explanatory model for
Alzheimer’s in which the central element is the synaptic toxicity of beta-amyloid
oligomers, rather than the toxicity of beta-amyloid fibrils agglutinated into
This hypothesis is based on at least two well
documented phenomena: a) in humans with Alzheimer’s, the high correlation
between the loss of synapses and the clinical severity of their condition, and
b) in animal models of Alzheimer’s, the observed rise in soluble beta-amyloid
levels in the cortex as signs of pathology increase.
using animal models of Alzheimer’s also have made many observations indicating
that the synapses might be affected negatively by this increase in beta-amyloid
oligomers. For example, physiological concentrations of beta-amyloid dimers and
trimers (but not monomers) have been found to induce a gradual loss of synapses
in the hippocampus.
other animal studies, using mice, synaptic losses reducing the effectiveness of
term potentiation (LTP), one of the molecular mechanisms underlying learning
and memory, were observed even before any amyloid plaques appeared. Oligomers
of beta-amyloid, which have low molecular weights and are non-fibrillar, also
can block LTP. These oligomers are also necessary and sufficient to temporarily
disrupt learned behaviours.
In 2005, Eric Snyder and
his team advanced knowledge a step further by showing that beta-amyloid oligomers
facilitate the absorption of the neuron’s NMDA
receptors into the cell body by endocytosis, thus reducing their availability
at the synapse. Snyder hypothesized that this process begins when the beta-amyloid
binds to the alpha-7 nicotinic receptor, which activates the protein phosphatase
2B. This protein then activates striatal-enriched tyrosine phosphatase (STEP),
which, by dephosphorylating the NMDA receptor, increases its endocytosis. Thus
this molecular cascade ultimately reduces the density of NMDA receptors at the
synapse, thereby reducing glutamatergic transmission and hence the LTP that is
the basis for synaptic plasticity.
exposure to high levels of beta-amyloid oligomers also causes shrinkage of the
dendritic spines—the protrusions from the neurons’ dendrites that
form the post-synaptic part of the synapses. This reduction in the density of
the dendritic spines is accompanied by a reduction in the level of debrin, a cytoskeletal
protein that, along with the actin
filament, modulates synaptic plasticity. An interesting detail: this reduction
in debrin can be blocked by memantine, a medication prescribed to Alzheimer’s
patients under the brand name Namenda, just as the administration of the antibody
to beta-amyloid also prevents this deterioration of the dendritic spines.
2009, researchers also established a possible link between the neuronal death
typical of Alzheimer’s and a mechanism
for eliminating excess neuronal connections that plays a predominant role
at the very start of brain development. Their hypothesis was that this mechanism
might be reactivated by some processes associated with aging, processes that involved
not beta-amyloid itself, but rather the release of the N-terminal fragment, which
lies adjacent to beta-amyloid on the APP molecule. This fragment would then trigger
a cascade of harmful molecular reactions by binding to a receptor called Death
Receptor 6 (DR6).
DR6, which is heavily expressed
in the parts of the brain affected by Alzheimer’s, was already known to
trigger the process called programmed cell death, or apoptosis (follow
the Tool Module link to the left). Studies had also shown that blocking the activity
of DR6 delayed axonal degeneration in vitro and also caused the redundant
synapses to remain in place in certain areas of the mouse brain.
findings suggested that the activation of the DR6 receptor by the N-terminal fragment
of APP might reactivate programmed-cell-death mechanisms that are normally active
at the very start of brain development. In this model, beta-amyloid plays a complementary
role, by degrading the synapses, rather than by killing the cells.
model proposed at about the same time traces the ultimate cause of Alzheimer’s
back beyond amyloid plaques to a disruption of the process of cell division. Thus
this model too involves the reactivation, later in life, of a process that normally
occurs very early in development—in this case, the differentiation
of stem cells into neurons. But mature neurons, which are well differentiated
in terms of their dendrites and axons, are clearly no longer suited to cell division.
Consequently, the reactivation of the processes that lead to cell division would
be fatal to the neurons in the brains of adults who have Alzheimer’s.
Tau proteins are far from the only
ones whose form, and hence function, can be altered by their degree of phosphorylation.
Indeed, phosphorylation is a very common means of regulating cellular mechanisms.
For instance, phosphorylation plays an indispensable
role in amplifying the number of signals received from extracellular stimuli,
the classic example being the activation of intracellular second messengers after
a neurotransmitter binds to its receptor. These second messengers often include
enzymes that phosphorylate the intracellular ends of the transmembrane ion channels.
This phosphorylation increases the time that these channels remain open, as occurs
reinforcement phenomena such as long-term potentiation.
example is the broader, ongoing role that phosphorylation plays in assembling
and disassembling the microtubules
of the cell’s cytoskeleton according to the current
phase of the cell’s division cycle. The stability of these microtubules
varies greatly over this cycle. During interphase, when the cell is not dividing,
the microtubule structure controls its form and physiology. But once the cell
starts dividing, its microtubules depolymerize to leave room for others that will
be built so that the chromosomes can be segregated and the cell can divide in
Phosphorylation is thus a post-translational
modification in proteins that, by causing a change in their form or enzyme activity,
enables their function to be modified.
But since the start of the 2000s, numerous
findings have begun to cast doubt on this hypothesis and lend more credence
to alternative explanations. The best known is probably the one that attributes
the primary role in Alzheimer’s pathology to the aggregation of tau proteins
to produce neurofibrillary
tangles. Without tau protein molecules to stabilize them, the neurons’
microtubules disintegrate, which disrupts
axonal transport and ends up killing the neurons. And loss of neurons is very
strongly correlated with the seriousness of the cognitive deficits displayed by
people with people with Alzheimer’s.
the mechanisms by which the tau protein molecules become detached from the microtubules,
many scientists believe that increased phosphorylation of the tau protein molecules
plays an important role. Indeed, researchers have observed that agglutinated tau
proteins are highly phosphorylated and that phosphorylation of tau proteins reduces
the strength of their bonds to the microtubules.
phosphorylation is a complex phenomenon that is involved in the regulation of
many processes, including neuronal development. Hence the specific role of phosphorylation
protein pathologies (also called “tauopathies") such as Alzheimer’s
is still the subject of debate. For example, some data suggest that phosphorylation
of tau protein molecules occurs after their aggregation, and that the
detachment of these molecules (from the microtubules) and their subsequent aggregation
are associated more with structural changes within them than with their phosphorylation.
But there is still a great deal of support for the hypothesis that phosphorylation
plays a fundamental role in tauopathies. For example, in these pathologies, tau
protein molecules develop new phosphorylation sites not found on the tau proteins
of healthy developing or adult cells.
Note that not
all of the known phosphorylation sites on the tau protein molecule are involved
in regulating its binding to microtubules. Examples of the sites that do have
an influence on this binding are site Thr181 (for the 181st amino acid, which
is a threonine) and sites Ser202, 214, 262, 324 and 356 (for the amino acid serine
at these respective positions).
The phosphorylation status of tau proteins depends
on the balance between the activities of two types of enzymes: protein kinases
(which add phosphate groups) and phosphatases (which remove them). Thus, on the
one hand, there will be kinases such as protein kinase A, phosphorylase kinase,
and glycogen synthase kinase 3, and on the other there will be serine and threonine
phosphatases whose antagonistic activities will also help to regulate tau protein
However, these enzymatic interactions affecting
the phosphorylation of tau protein molecules are very hard to study in vivo,
for several reasons. First of all, the activity of kinases in situ often
depends on their own phosphorylation status. In other words, the activity of kinases
that can phosphorylate the tau protein is itself dependent on the activity of
other kinases. These other kinases, which participate in other cascades of biochemical
reactions, can thus influence the phosphorylation status of tau proteins indirectly
even though they do not interact with them directly. Second, phosphatases can
also dephosphorylate and thus deactivate the protein kinases that can phosphorylate
tau proteins, so here again, there are possible indirect effects.
several studies show that there are some co-factors that also can modulate the
status of the tau protein by increasing or decreasing its phosphorylation. Examples
include the intracellular levels of calcium, cyclical AMP, and phospholipids that
influence kinases such as protein kinase A. These co-factors probably alter the
three-dimensional structure of tau proteins, possibly making them better substrates
for certain kinases.
As if all that were not complex
enough, the phosphorylation of tau proteins can also by modulated by the physiological
state of the cell. When the cell is under stress, phosphorylation of tau proteins
from Trends in Neuroscience
That said, researchers are beginning to take a
closer interest in certain specific tau-protein-related enzymes that may be implicated
in Alzheimer’s. Many of these enzymes act prior to the biochemical cascade
and promote both the aggregation of tau proteins and the formation of amyloid
plaques. One such enzyme is glycogen synthase kinase 3 (GSK-3), a protein kinase
responsible for the phosphorylation of a number of proteins, including the tau
protein. The reason for the interest in GSK-3 is that in addition to its effect
on the tau protein, it also regulates the cleavage of APP
(the precursor of beta-amyloid), reduces neurogenesis,
and increases apoptosis (follow the Tool Module link to the left). All
of these phenomena are closely associated with the cognitive deficits seen in
Researchers have also discovered
some mutations in the gene for the tau protein. These mutations result in tau
protein molecules that agglutinate more and bind to microtubules less—another
set of conditions conducive to the detachment of tau proteins and their aggregation,
resulting in neurofibrillary degeneration.