Using the Immune System to Fight Alzheimer’s Disease

Our immune system is amazing. It protects us from an ever-changing multitude of foreign invaders that want to colonize our bodies. Parasites, fungi, bacteria, even viruses are repulsed or destroyed by the protective cells of the immune system and the proteins they produce. So it is not surprising that researchers would attempt to activate this powerful ally in the fight against Alzheimer’s disease.

But why does the immune system need activation? Why doesn’t it just attack Alzheimer’s disease on its own?

Basically, the immune system is designed to protect the body from foreign invaders, and is programmed to ignore anything produced by the body itself. Since Alzheimer’s disease involves proteins that are self-produced, the immune system does not normally become involved.

But it is possible to activate an immune response. Sometimes this happens unintentionally. Auto-immune disorders like Muscular Dystrophy, Lupus, and Lou Gehrig’s Disease are abnormal attacks on a body by its own immune system. In these disorders, the immune system has somehow become confused about what is foreign and what is not.

When a researcher wants to activate the immune system against Alzheimer’s disease, they begin with immunization—the same method used when we vaccinate children against polio or mumps, measles, and rubella.

In Alzheimer’s immunization research, small portions of Aβ are injected under the skin along with molecules that irritate the immune system and provoke an immune response. Once the response begins, antibodies are produced that target all the compounds that have been injected. A second injection follows a week or two later. That injection contains only Aβ protein, so all the antibodies made this time will target Aβ.

In Alzheimer’s disease, those antibodies are meant to attack the plaques by attaching to the Aβ and taking it out of circulation before it can form plaques, or by attaching to the plaque itself and marking it for destruction by macrophages (the rubbish trucks of the immune system, macrophages gobble up bacteria, proteins, or plaques that have been pointed out to them by the attachment of antibodies.)

Years ago, Aβ immunization was shown to be amazingly effective in tests on mice, but when tried on humans it caused serious side effects including brain inflammation and even death. Human testing was stopped immediately.

Since then researchers have been working to make “designer antibodies” that will be able to clear away plaques without the negative side effects.

The designer antibodies can be delivered to the brain in two ways:

Active immunization involves actually injecting a person with Aβ that has been modified so the antibodies produced will not be harmful. Active immunization would work like any other vaccination—a few shots, and you would be protected (or treated) for years.

Passive immunization involves growing the designer antibodies in the laboratory (using cell culture techniques) and injecting them periodically. The advantage to passive immunization is that the amount of antibody at work can be carefully controlled. The disadvantage is that it is more costly and involves repeated injections. However, for people who have Alzheimer’s, passive immunization may someday be the treatment of choice. This is because in the elderly, the immune system is not as effective as in the young, and it might not always be possible to reliably activate the immune response.

The true potential of immunotherapy for Alzheimer’s disease remains to be seen, but it is an area of active research and excitement.

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Slowing the Formation of Beta Amyloid Plaques

Beta amyloid plaques are deposits of abnormal, highly insoluble protein.  They form in the space between cells in the Alzheimer brain, and are one of the characteristic hallmarks that identify Alzheimer’s disease at autopsy. There are drugs being developed to slow the formation of these plaques and to speed the clearance of the beta amyloid deposits. To find compounds that prevent the clumping of beta amyloid, are reasonably nontoxic, and are effective when taken orally has been difficult.

The company did WHAT??

One particularly interesting drug was called tramiprosate. In the laboratory, it attaches to Aβ and stops clumps from forming. But when tramiprosate was tested in North America on volunteers with mild-to-moderate Alzheimer’s, it was not effective. The company developing the drug, Bellus Health, discontinued a similar study in Europe. Instead, in 2008, they released tramiprosate as an over-the-counter neutriceutical (a nutritional supplement or herbal remedy) said to protect memory functions. They called it Vivimind. There was protest from the scientific community over this release, but it was essentially ignored.

Another drug preventing the clumping together of Aβ is called Clioquinol (PBT1). This drug was highly toxic in initial studies, but a new version of it, PBT2, is showing good results in animal studies. It is not uncommon for a drug to be developed in several versions. Small changes in chemical structure that do not significantly change the effect of a drug in the laboratory can make a big difference when that same drug is tested in animals or humans. PBT2 looks promising.

Next time, drugs that clear away amyloid plaques—using the immune system to fight Alzheimer’s!

About All Those Scientific Terms…

Sorry, folks. There aren’t many cute/funny diagrams to illustrate these terms. And my graphic arts skills don’t stretch that far.

It’s been brought to my attention that the scientific terms are beginning to pile up a bit and get in the way of understanding the concepts I am trying to share. (Thanks, Jlynn.) So today let’s try to clear away some of the clutter.

There are two ways to go with scientific terms. You can tell yourself they are only names—just monikers attached to bits of matter—which is essentially true. Or you can try to understand where they came from.

Understanding the origin of a name is only useful if it helps you connect the name and the thing being named. So let me take a shot at helping with that.

BETA-AMYLOID:

Amyloid is a generic term referring to clumps of insoluble protein. You can have amyloid deposition in many disorders, as well as a result of repeated medical procedures like kidney dialysis. The specific protein clumping up and getting deposited varies from disorder to disorder.

All amyloids share certain traits. Most important is insolubility. They are tremendously hard to dissolve, which is the reason deposits build up. The reason they are insoluble has to do with their abnormal 3-D shape, called the beta-pleated-sheet conformation. To a chemist, those italicized words carry meaning and significance. To you and me, all they need to say is insoluble protein.

The name of the specific protein in the amyloid deposits of Alzheimer’s disease is beta-amyloid protein (a.k.a. beta amyloid, nicknamed Aβ for short). There is a long (and boring) story about how that name came to be, but suffice it so say that after much initial disagreement, beta-amyloid is the name that was finally generally agreed upon.

APP:

APP stands for amyloid precursor protein (or amyloid protein precursor—depending on whose paper you are reading). This is a big protein (in the neighborhood of 700 amino acid subunits long).

The much smaller (40-42 amino acid subunits) beta-amyloid protein (a.k.a. Aβ) is a small piece snipped out of APP by the secretases discussed last time.

ALPHA, BETA, and GAMMA SECRETASE:

These are the enzymes that act like scissors to cut APP.

Alpha secretase cuts right in the middle of the Aβ part of APP. Any APP molecule that is cut by alpha secretase has had its Aβ portion cut in two, so if half of the APP molecules in a brain are cut by alpha secretase, the potential for Aβ production has been cut in half.

On the opposite side of the coin, beta and gamma secretase work together to free the Aβ section from the big old APP molecule. Beta secretase cuts one end free, and gamma secretase cuts at the other end, releasing Aβ. You only need to stop one of this pair from working to decrease Aβ production.

Together, these three enzymes are called secretases because the protein pieces they cut free are released outside the cell (that is, they are secreted— 😉 .   We scientists usually go for the obvious when naming things.)

DRUG NAMES:

I’m afraid I can’t be much help with these…

When drug names look like catalog numbers, that is pretty much what they are—someone is testing a bunch of similar compounds and has numbered them. There is no good way to recall these except to have a good memory. Personally, I don’t try to keep them straight in my brain; I just look them up when I need them.

Chemical names of drugs are sometimes used. These carry useful information only if you are chemist enough to understand them… usually I am not that much of a chemist. I treat these the same as the catalog-type names.

Brand names of drugs are assigned by the companies selling them. While these do sometimes carry meaning, more often they are just made up by some marketing guru employed by the pharmaceutical company.  If you are an Alzheimer’s caregiver, you probably recognize these more readily than I do. Some of the more common I carry in my brain. But even with those, I look them up to be sure I have it straight when writing about them.

Did that help?

I hope so. Next time we’ll get back in sequence and talk about drugs being developed to prevent aggregation and/or promote the breakdown and removal of beta amyloid deposits.

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–Susan.

Reducing Beta-Amyloid in Alzheimer’s Disease Brain, part 1

Last week I wrote about beta-amyloid protein, one of the two proteins (the other is tau)that is misfolded in Alzheimer’s disease. “Misfolded” refers to the fact that in Alzheimer’s disease, these two proteins are found in abnormal 3-D forms that are related to the dysfunction and death of brain cells.

Alpha, beta, and gamma secretase process APP

This week’s post is about the specific enzymes that act like scissors, cutting beta amyloid out of the larger APP protein molecule from which it is released. Those enzymes are named alpha, beta, and gamma secretase. The diagram shows where each of those enzymes cuts the APP molecule.

As you can see, beta and gamma secretase produce the protein fragment we call beta-amyloid and alpha secretase cuts right through the middle of the beta-amyloid segment, thus stopping beta-amyloid formation.

Developing drugs to target beta secretase

The first step in producing beta-amyloid—both the harmless Aβ40 and the Aβ42 that clumps up in insoluble deposits around brain neurons—is the cut made by beta secretase just outside of the membrane. (The aqua rectangle in the diagram represents a portion of cell membrane.)

Much effort has been expended to produce drugs that will stop beta secretase from making that initial cut. This is not a simple matter because APP is not the only protein that beta secretase cuts. In fact, beta secretase is involved in the processing of many proteins, some of which are important to neuronal function. Stopping the cutting, or cleavage, of APP without interfering with the cleavage of other proteins is difficult. Making the problem harder is the fact that most good of beta secretase will not travel through the blood brain barrier, a glial cell construction that determines which molecules from blood are allowed to enter the brain.

Some drugs for type 2 diabetes inhibit beta secretase

The good news is that some oral drugs used to control type 2 diabetes are inhibitors of beta secretase. Those are Rosiglitazone and Pioglitazone. Both of these enter the bloodstream, but Rosiglitazone might not be able to get into brain—it may not cross the human blood brain barrier. Pioglitazone can enter brain.

Although approved for use in type 2 diabetes, these drugs have not been approved for use in Alzheimer’s. Both were being tested on persons with Alzheimer’s disease, but no positive results have been reported. Recently, the FDA warned that cardiac risks were associated with Rosiglitazone use, and since it wasn’t helping brain function, studies on Rosiglitazone were discontinued.

Pioglitazone is still being tested on Alzheimer’s patients in phase two clinical trials. A new drug, CTS-21166, is being tested in healthy non-demented volunteers (phase 1 clinical trials). In these volunteers CTS-21166 reduces the amount of beta amyloid found blood plasma, without significant negative side-effects.

Developing drugs to target gamma secretase

Gamma secretase makes the final cut that releases beta amyloid from the APP molecule. Inhibiting the function of gamma secretase is problematic because most inhibitors won’t cross the blood brain barrier to enter brain, and because some very important proteins (in addition to APP) rely on processing by gamma secretase to make them fully functional. One of those proteins, called Notch, is so important that removing it from mice is lethal. For this reason, many laboratories are working to find drugs that will modulate or control the activity of gamma secretase, without shutting it down completely. The best of these drugs inhibit gamma secretase cleavage of APP with little or no reduction in cleavage of Notch.

Drugs that target gamma secretase, without stopping Notch processing

Several such drugs are in clinical trials now. Phase one testing (on healthy non-demented volunteers) is being performed on Begacestat and PF-3084014. Both these drugs reduced concentrations of beta-amyloid in blood plasma, but not in cerebrospinal fluid (indicating they may not be crossing the blood brain barrier). Another drug, CHF-5074, has no effect on Notch processing at all and reduces brain Aβ while improving behavioral performance in animals. This drug is also being tested in phase 1 trials. No results are available yet.

In testing on Alzheimer’s individuals (phase 2 and phase 3 trials). A drug called BMS-708163 decreased beta-amyloid in cerebrospinal fluid. Another drug, tarenflurbil, was tested but had no positive effects. Tarenflurbil’s failure to perform may have been due to confounding factors in the study, and it will probably be re-tested.

Finally, a simple sugar (monosaccharide), NIC5-15, is being tested. This sugar is safe, but whether it is effective in reducing beta-amyloid production remains to be seen.

Reducing beta-amyloid by stimulating alpha secretase

A large number of drugs are known that stimulate alpha secretase activity. Since alpha secretase chops APP in the middle of the region that would become beta-amyloid, stimulating alpha secretase activity should decrease Aβ formation. These drugs are entering phase 1 clinical trials; no results are available yet.

Next time…

It should be possible to decrease beta amyloid production by using the kinds of drugs discussed today. But equally important is preventing beta amyloid from clumping and forming deposits in brain. Next time, we’ll look at drugs that prevent aggregation and/or promote the breakdown and removal of beta amyloid deposits.

Information about specific drugs is from the review Alzheimer’s disease: clinical trials and drug development, by Francesca Mangialasche, Alina Solomon, Bengt Winblad, Patrizia Mecocci, and Miia Kivipelto (Lancet Neurol 2010; 9: 702–16).