ApoE, a protein 299 amino acids long, plays the
role of a cholesterol transporter and enables neuronal repair by transporting
the necessary fats. This protein is also thought to be important in other vital
processes in the central nervous system, such as myelination,
dendrite growth, and synaptic
Many molecules are certainly involved in the
development of Alzheimer’s, and new candidates are announced regularly in
the media. For example, in 2009 and 2010 alone, there was much discussion of leptin,
a hormone that the body’s fat cells produce after meals and that causes
appetite to decrease. In one study, the subjects who had the lowest levels of
leptin were shown to be more likely to develop Alzheimer’s.
in 2009 and 2010, mouse studies by Rémi Quirion and Jonathan Brouillette
showed that those animals whose gene for transthyretin (TTR) was
less active were more likely to display memory deficits than those in which this
gene was more active.
Meanwhile, researchers at the Buck Institute for
Age Research and the CNRS (French national centre for scientific research) focused
their efforts on netrin-1,
known to be involved both in the development of the nervous system and in the
regulation of cancers. In mice used as models for Alzheimer’s, injecting
this molecule reduced the presence of amyloid plaques and restored lost cognitive
These are just three of the molecules that
are considered to offer promise as treatments for Alzheimer’s. There are
| || |
plaques were described by Alois Alzheimer very early in the 20th century,
they did not begin to give up their secrets until 1984, when American
research pathologist George Glenner and his team characterized their main component:
the peptide beta-amyloid.
Soon after, in 1992,
Hardy and Higgins assigned a central role to beta-amyloid and its precursor, APP
(amyloid protein precursor) when they formulated what was to become the most famous
hypothesis about the origins of Alzheimer’s-type
dementia: the amyloid-cascade hypothesis. According to this
hypothesis, the production and subsequent aggregation of beta-amyloid are the
ultimate source of the disorders experienced by people with Alzheimer’s.
pathologies associated with the tau protein, as well as other
mechanisms proposed to explain Alzheimer’s, are thus regarded as processes
downstream from this amyloid cascade.
The gene for
beta-amyloid’s precursor, APP, is located on chromosome 21 and is expressed
in virtually every tissue in the body. This gene, after being transcribed into
molecules of messenger RNA which are then spliced in various ways, leads to the
production of glycoproteins ranging in length from 695 to 770 amino acids; the
form with 695 amino acid predominates in the neurons of the brain.
is classified as part of a large family of proteins known as transmembrane proteins,
because it passes from the inside of the neuron (the cytoplasm) through the cell
membrane to the outside. APP’s long N-terminal segment is located outside
the neuron, and its short C-terminal segment is located inside. As its full name,
amyloid protein precursor, suggests, APP can be cleaved by enzymes to produce
other, smaller proteins, including beta-amyloid.
|Two different kinds of
enzymes cleave APP at different sites to produce two different peptides (small
proteins). Alpha-secretases release the peptide APPs-alpha, which
is believed to have neuroprotective properties and to play a helpful role in neuronal
plasticity. Beta-secretases, (also known as beta-amyloid
cleaving enzymes, or BACEs), working together with gamma-secretases,
release the peptide beta-amyloid. || |
Adapted from Sisodia 2002
cleavage of APP by beta-secretases is referred to as its amyloidogenic metabolic
pathway, while its cleavage by alpha-secretases is is referred to as its non-amyloidogenic
metabolic pathway. The latter may be beneficial, because it may prevent APP from
According to the amyloid-cascade
hypothesis, a malfunction in the amyloidogenic pathway results in increased production
of the long form of the peptide beta-amyloid—the one with 42 amino acids.
Compared with the normal form, which has only 40 amino acids, the form with 42
agglutinates more readily into amyloid plaques. During the mild
and moderate stages of Alzheimer’s disease, the form with 42 amino acids
predominates in these plaques. It is only later in the progress of this dementia
that substantial amounts of the 40-amino-acid form are found there as well.
according to this hypothesis, the aggregation of 42-amino-acid beta-amyloid first
into fibrils (through the juxtaposition of their beta-pleated
sheets), and then into fibrillary plaques, poisons the neurons by allowing
too much calcium to enter them, causing their death by necrosis or apoptosis.
The accompanying inflammatory reaction, causing the cells of the immune system
to secrete neurotoxic free radicals, would aggravate this lethal effect.
according to the amyloid hypothesis, the beta-amyloid plaques produce all of the
subsequent pathology associated with Alzheimer’s, including neurofibrillary
tangles. For many years, this hypothesis represented the dominant paradigm
for research on Alzheimer’s, but it has
now shown its limitations and become the subject of debate.
a number of proven facts do continue to support this hypothesis. For example,
in 1991, John Hardy’s team discovered that certain cases
of the family form of Alzheimer’s disease are caused by APP mutations.
In addition, these mutations result in increased production of the long form of
beta-amyloid, which is more susceptible to aggregation. These two observations
support the idea that the source of the cascade of events that leads to Alzheimer’s
can be found in mutations that affect the production of beta-amyloid.
the most common cases of the family form of Alzheimer’s come from mutations
in the gene for presenilin 1 (PS1), located on chromosome 14, and in an analogous
gene, called PS2, located on chromosome 1. In 1996, various research teams showed
that these mutated PS1 and PS2 proteins also favoured the production of the long
form of beta-amyloid, probably by interacting with the catabolism of APP.
all indications are that the transmembrane proteins resulting from the genes for
presenilin 1 and 2 lie behind the enzymatic activity of the gamma-secretases,
which cleave APP at a site that indeed is located somewhere in the middle of the
Though not determined by dominant
autosomal mutations the way the family form is, the sporadic form of Alzheimer’s
is nevertheless influenced by certain genes, among which the gene for apolipoprotein
E (ApoE) is the most clearly implicated (see sidebar). In 1993, Judes Poirier’s
team showed that the presence of one of the three
main forms of the protein ApoE, ApoE4, constitutes a risk factor for both
the family form and the sporadic form of Alzheimer’s. Various mechanisms
might explain this harmful effect of the ApoE4 variant, including a decrease in
the elimination of the beta-amyloid peptide. ApoE also seems to be implicated
in forming the amyloid fibrils that agglutinate into plaques. It is also regarded
as a co-factor in amyloidogenesis.
in mice, have shown that ApoE4 reduced the complexity of the dendritic trees of
the cortical neurons and the density of the dendritic spines. Other studies also
suggest that ApoE4 is less effective than other variants of ApoE in repairing
neurons and that it disrupts the induction of long-term
potentiation in the hippocampus.
factor that may predispose individuals to Alzheimer’s and that is attracting
increasing attention is the gene for clusterin, also known as apolipoprotein J.
This versatile protein has many properties enabling it to protect and repair other
proteins that have folded improperly. It may thus bind to the peptide beta-amyloid
and prevent it from forming the fibrils that give rise to plaques. Clusterin is
also involved in eliminating beta-amyloid peptides and their fibrils.
the late 1980s, the expression of clusterin has been known to be higher in people
with Alzheimer’s, as if their bodies were trying to prevent the development
of the amyloid plaques. In the years just prior to 2010, two international consortiums
also compared nearly 600 000 genetic markers in over 20 000 people and confirmed
the important role that clusterin seems to play in Alzheimer’s.
aside from these data on the production and aggregation of beta-amyloid, there
are many observations that are hard to reconcile with the amyloid-cascade hypothesis.
For example, even if mice that have the mutations associated with the family form
of Alzheimer’s disease produce excessive amounts of the 42-amino-acid form
of beta-amyloid (and develop the corresponding amyloid plaques), most of them
do not experience significant neuronal losses, show little phosphorylation
of the tau protein, and do not have the neurofibrillary tangles that the amyloid
hypothesis would predict. And the same inconsistency is observed in certain parts
of the human brain, such as the cerebellum, which can have large numbers of amyloid
plaques while displaying none of the associated phenomena predicted by the amyloid
Significant fuel is added to the controversy
surrounding this hypothesis by the poor correlations between the spatial and temporal
dynamics of plaque formation and the severity of the observed cognitive deficits.
In contrast, cognitive decline in Alzheimer’s is very highly correlated
with synaptic loss. This is especially interesting in relation to studies concerning
that the soluble, non-fibrillar form of beta-amyloid plays in the destruction