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Les troubles de l'esprit
Depression and Manic Depression
Anxiety Disorders
Alzheimer’s-type Dementia

HelpLink : The synaptic AB hypothesis of Alzheimer diseaseLink : Beta amyloidLink : Evidence Points to Amyloid Beta as the Key to Alzheimer Disease
Link : Detailed 3D image of Alzheimer's pathologyLink : Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behaviorLink : After Alzheimer's amyloid hypothesis, introduction. An unabridged original edition of the manuscript, published in Journal of Alzheimer's diseaseLink : Alzheimer's recapitulates brain development
Link : Amyloid-B and tau in Alzheimer’s disease
Researcher : Laboratory for Alzheimer's Disease Research : Peter Davies, PhD
Experiment : Synaptic transmission block by presynaptic injection of oligomeric amyloid betaExperiment : Natural Oligomers of the Alzheimer Amyloid-_ Protein Induce Reversible Synapse Loss by Modulating an NMDAType Glutamate Receptor-Dependent Signaling PathwayExperiment : Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's diseaseExperiment : Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers
Original modules
Tool Module : Prospective Treatments for Alzheimer'sProspective Treatments for Alzheimer’s
Tool Module : Apoptosis Apoptosis (Programmed Cell Death)

Once released from its precursor, APP, by the action of secretase enzymes, the peptide beta-amyloid becomes a soluble monomer (that is, it consists of single peptide molecules rather than chains of two molecules or more). These monomeric molecules of beta-amyloid are also referred to as amyloid-derived diffusible ligands (ADDLs).

However, 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.

Link : Amyloid aggregation mechanisms

Diabetes is known to be a risk factor for Alzheimer’s. It is also known that people with Alzheimer’s produce less insulin in their brains, and that their neurons are less sensitive to insulin.

In 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.

This 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.

Link : Insulin may help treat Alzheimer’s


Many scientific observations have shown an association between the aggregation of plaques of beta-amyloid fibrils and the cognitive deficits that characterize Alzheimer’s. However, where and when these amyloid plaques develop in the aging brain is rather poorly correlated with the gradual appearance of the memory losses and other symptoms of Alzheimer’s. Moreover, some cognitively normal individuals develop amyloid plaques without any trace of the neuronal damage associated with them.

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).

The synaptic 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 plaques.

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.

Studies 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.

In other animal studies, using mice, synaptic losses reducing the effectiveness of long- 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.   


Adapted from
Nature Neuroscience 8, 977 - 979 (2005)


Prolonged 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.


Around 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.

These 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.

Another 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.


Link : MALADIE D’ALZHEIMER : pas encore de médicamentLink : Neurobiological pathways to Alzheimer's disease: amyloid-beta, Tau protein or both?Link : Tau phosphorylation: thèse de Patrice DelobelLink : Amyloid-B and tau in Alzheimer’s disease
Link : Could Alzheimer's be influenced by something so ordinary as chronic stress?Link : Pin-pointing APP ProcessingLink : Glycogen synthase kinase 3 (GSK-3)
Experiment : Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's diseaseExperiment : Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer's diseaseExperiment : Enhanced Neurofibrillary Degeneration in Transgenic Mice Expressing Mutant Tau and APP
Original modules
Tool Module : ApoptosisApoptosis (Programmed Cell Death)

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 in synaptic reinforcement phenomena such as long-term potentiation.

Another 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 two.

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.


For over a decade, the amyloid-cascade hypothesis dominated research on Alzheimer’s. According to this hypothesis, Alzheimer’s is caused by the accumulation of amyloid plaques (or of beta-amyloid oligomers) that lead to neurofibrillary tangles and then neuronal death.

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.

As regards 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.

However, phosphorylation is a complex phenomenon that is involved in the regulation of many processes, including neuronal development. Hence the specific role of phosphorylation in tau 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).

Neurofibrillary degeneration (NFD) is associated with hyperphosphorylation of and new phosphorylation sites on the tau protein.  Source: Tout sur Tau (Association pour le Développement des Neurosciences Appliquées)

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 activity.

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.

Moreover, 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 increases sharply.

Adapted 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 Alzheimer’s.

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.
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