ADDL Paper

Ashley Edwards

FYS Molecular Machines

ADDLs

Amyloid beta-derived diffusible ligands, ADDLs, bind in groups to neurons in the brain and are thought to cause Alzheimer’s disease. If ADDLs could be stopped from binding to the neurons, then the progression of Alzheimer’s disease could possibly be slowed down or even stopped completely. Acumen, a pharmaceuticals company, has already begun research to try and determine just how ADDLs can be stopped from making damaging clusters in the brain. Since aptamers can be selected to bind to certain things, if they could be selected to bind to the neurons and proteins that ADDLs bind to, then they would be very effective at helping stop the spread of Alzheimer’s in the brain.

Merck, a company that has already entered into a contract with Archemix, the leading company in aptamer research, has promised 48 million dollars for research into ADDLs and will give another 48 million dollars if a vaccine is developed. Merck and Acumen, the leading company in ADDL research, have entered into a contract where Merck will have exclusive rights to Acumen’s ADDL technology. Acumen is working on an assembly blocker and a binding inhibitor to stop the ADDL from initiating Alzheimer’s disease. The assembly blocker would work to stop the production of the oligomers, so that the ADDL would never be able to form. As this is a protein-protein interaction, it would be very difficult to target, but aptamers again look like a promising choice as a target molecule. The binding inhibitors would prohibit the ADDLs from binding to the neurons. This would work by either having a molecule bind to the ADDL where it would bind to the neuron, or having a molecule bind to the neuron. Again, aptamers might prove useful as a target molecule for either of these options. Acumen has not discussed using aptamers in either of their projects, but that does not mean that it isn’t a viable option. Acumen has discussed their selection process for molecules that might potentially bind to the ADDLs, but they have not yet released what molecules they are using in the selection process. Similar to SELEX, their selection process consists of placing a large quantity of small molecules into solutions with different ADDLs to determine whether or not they bind. They also test them in vitro to make sure the molecules would not be potentially toxic. Acumen would also then test whether or not those ADDLs would bind to the neurons or not, to make sure that the molecule was binding in the correct place. They have not yet released their plans for the selection of molecules to bind to the receptor sites on the neurons.

Both Acumen and Merck seem to be at the forefront of medical technology, and if successful, could make Alzheimer’s disease obsolete in a few years. Merck has seen some hardships in the past few years, with a withdrawal of Vioxx, an arthritis painkiller, and multiple lawsuits that claimed Merck did not properly warn the public about the risk of heart attack as a side effect of Vioxx. As a result, their stock went down starting around October of 2003, and has never fully recovered, although it is well on its way to surpassing where it was before the crash. Both Acumen and Merck would be excellent companies to invest in because a cure for Alzheimer’s disease would have profound effects on society and would generate a lot of revenue. Merck seems to be very involved in other risky, high-tech, medicine research that could pay off big in the next ten years or so. Archemix, the aptamer research company, has also entered into a contract with Merck. The main focus of their agreement is research into targeting cancerous cells using aptamers and if this is successful, then obviously both Merck and Archemix will begin making millions. All three of these companies would be great investments, because although risky, they have enormous pay-offs if successful. These new technologies will most likely provide the basis by which almost all diseases will be treated within the next ten to twenty years, and getting aboard now would be wise. Before investing, however, it is always smart to look at what exactly the companies are working on.

ADDLs are sticky, insoluble proteins that can clump together in messy groups in the brain and cause large build-ups of sticky fibers that attach themselves to neurons. Amyloid beta is a peptide made up of amino acids that forms after sequential cleavage of the amyloid precursor protein (APP) by the β- and γ-secretases. APP is a transmembrane glycoprotein, which means it is made up of a protein and a carbohydrate. The amyloid beta protein can then go through proteolytic processing, which would cause the digestion of proteins by enzymes. The exact proteolytic processes that cause ADDL to form are most likely the mutation of Ab peptides that have 40 peptides into ones with 42 peptides. This mutated form can then bind to neurons and cause Alzheimer’s and occasionally the death of the neuron. By attaching to the neuron, the ADDLs disrupt the normal signaling and cause the memory problems and dementia in Alzheimer’s disease.

The tau protein, which is a microtubule-associated protein normally found in the brain, has also been thought of as a cause of Alzheimer’s. Like ADDLs, it is found in high concentrations in the brain of patients with Alzheimer’s because it occasionally goes through hyperphosphorylation that causes large groups of tangled tau proteins and damages neurons. However, Jan Naslund, Ph.D., from Rockefeller University in New York, has done research on the brain tissue of many patients and she argues that ADDLs are most likely involved in the very early onsets of Alzheimer’s disease and might be the cause of the hyperphosphorylation of the tau proteins. The tau protein tangles then bind to the neurons, much like the clumps of ADDLs do, and further disrupt the signaling and therefore speed up the process of memory damage.

ADDLs are thought to interfere with long-term potentiation as an effect of binding to the neurons. Long-term potentiation is involved in spatial memory and is essential to learning. The ADDLs are also most likely to affect the hippocampus, and therefore affect the spatial navigation. Because the ADDLs affect these two things, researchers believe that they are the cause of synaptic memory formation loss and eventually lead to the dementia in Alzheimer’s patients. High concentrations of ADDLs have also been tied to the destruction of nerve cells that never regenerate, causing the slow deterioration. Below is a figure depicting the amyloid beta clumps that interfere with the neuron activity. If the clump grows large enough, it can cause the death of the nerve cells. The oligomers are also shown causing damage to a neuron, and those oligomers would most likely eventually turn into a clump of amyloid beta which would further damage the neurons. A clump of tau proteins is also shown in this diagram.

In order to stop the amyloid beta from forming ADDL, many solutions have been proposed. β- or γ-secretase inhibitors would stop the cleavage of APP and therefore would stop the production of amyloid beta and its mutations. Acumen is also working on inhibiting the production of oligomers so that the amyloid beta clumps would never form. Aptamers could possibly be selected to bind to whatever it is that ADDLs bind to, but at this point it is unclear if there is a specific site they bind to on the neurons, or if large clumps just happen to form sporadically. An immune attack on the ADDLs has been discussed, and since aptamers are also used as escorts, they could carry ADDL destroyers and could be selected to bind to the ADDL fibers.

ADDLs are almost universally agreed upon by scientists to play some role in the development of Alzheimer’s disease. Although there is dispute about whether the tau protein plays a larger role than the ADDLs, hopefully the scientists at Northwestern University and in Acumen are correct about ADDLs triggering the tau proteins. With the research of Acumen and the support of Merck, Alzheimer’s might become a thing of the past, and if you join now, you might be able to reap the economic benefits.

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