The misfolded proteins of Alzheimer’s Disease: Beta-Amyloid

In Alzheimer’s disease there are problems in passing messages from neuron to neuron (impaired synaptic transmission), problems caused by a lack of energy molecules in the neurons (mitochondrial dysfunction), and problems caused by misfolded proteins which cannot be degraded by the cell, and so build up in the brain, forming abnormal protein deposits. The misfolded proteins of Alzheimer’s disease—proteins that adopt three-dimensional shapes that are dysfunctional—are beta-amyloid and tau.

Misfolded beta-amyloid protein, the primary component of the senile plaques of Alzheimer’s disease, is the topic of today’s post.

Two kinds of beta-amyloid protein

Beta-amyloid protein is found in both normal brain and Alzheimer brain. There are two primary varieties of this small protein. The most common form, only forty amino acid subunits long, is called Aβ 40. Ninety percent of all beta-amyloid is Aβ 40.

The second variety, which makes up only ten percent of the beta-amyloid in normal brain, is forty-two amino acid subunits long and is called Aβ 42. For some reason those two extra amino acid subunits cause Aβ 42 to be prone to adopting a three-dimensional shape called the beta-pleated sheet conformation. Beta-pleated sheet proteins tend to clump together into insoluble aggregates which brain cells are unable to efficiently degrade. These aggregates form in the spaces outside brain cells, and are called senile plaques.

Changes in the ratio of Aβ 42 to Aβ 40

Many tests have shown that in Alzheimer’s disease the ratio of Aβ 42 to Aβ 40 is increased, making it easier for senile plaques to form. There are three ways this could happen:

1) the brain could be producing more Aβ 42,

2) the brain could be producing less Aβ 40,

or 3) the degradation of Aβ 42 could be impaired.

(If you are thinking, “Wait a minute! Couldn’t the degradation of Aβ 40 be increased?” you are correct. But this is not a likely cause since Aβ 40 is normally degraded very effectively anyhow.)

Approaches to drug discovery concentrate on these (first) three possibilities.

Why all three?

Not every case of Alzheimer’s dementia is caused by the exact same problem(s). In fact, it seems more likely that Alzheimer’s is caused by combinations of problems, and can develop from different combinations in different people. Thus it makes sense for the researchers fighting this terrible disorder to investigate all the roads that may lead to useful treatments.

Production of Aβ 40 and Aβ 42

Beta-amyloid is a short portion of a much longer precursor protein. The precursor is simply called Amyloid Precursor Protein, or APP. It is much easier to show you how beta-amyloid is produced than to tell you. So please look carefully at the diagram below.The aqua colored rectangle represents a section of cell membrane. APP is an integral membrane protein–meaning that it runs through the membrane from one side to the other. Alpha, beta, and gamma secretase are three of the enzymes that process APP. Specifically, they cut through the APP amino acid subunit string at the points shown by the white arrows.

You will notice that alpha secretase cuts right through the middle of Aβ, destroying both the 40 and 42 forms.

Beta and Gamma secretase produce Aβ. First the beta secretase cuts the right end, and then the gamma secretase cuts the left end, freeing the Aβ.

Each of those secretases is a target for drug development. More on that next week.

By the way, what I have been sharing here is common knowledge in the field of Alzheimer’s research. To list all the people who contributed to building the knowledge we have up to this point would require, quite literally, volumes. However, if you want a reference or two to peruse, and you have access to a medical library, I would be happy to search a few down for you. Just tell me what particular portion of this information you want to pursue. Also, much of the early research on Alzheimer’s is now open access and can be read by anyone via the internet.

Stay in touch.


Developing new drugs for Alzheimer’s Disease: Targeting misfolded proteins

The search for new drugs

When scientists search for new drugs, they begin by looking at the disease or disorder in question. If the cause of a disorder is known, research focuses on attempting to eliminate it. But if that doesn’t work, or if a scientist is studying a disease like Alzheimer’s, where the cause is not known, then she begins to look at the major problems or symptoms of the disease. Three of the major problems in Alzheimer’s disease are 1) synapses that don’t work properly, 2) neurons that lack the energy they need to function, and 3) misfolding of specific proteins.

Two weeks ago, I wrote about the synapses and drugs that directly affect synaptic transmission. To see that post, click here. Last week, the topic was the energy deficit in Alzheimer neurons, and the search for drugs that enhance mitochondrial function. You can read about that here.

Today, I want to begin talking about the misfolded proteins of Alzheimer’s disease. It’s a complicated topic, so we’re going to approach it bit by bit. First, we need some background information:

For proteins, folding properly is a big deal

When your cells make proteins, they connect protein subunits (called amino acids) together like beads on a string. There are twenty common subunits, each with a different 3-D shape. The subunits used and the order in which they are strung determines many of the traits of the protein made.

Now this is the part that is important to understand… The function of a protein depends on its three-dimensional shape.

When proteins are being made, there is an entire class of helper proteins (called chaperones) who have the important job of making sure the new proteins get folded into their proper functional shapes. (Yes, “who.” I fully intend to talk about proteins as if they were people. Grammarians will just have to deal with it.)

But proteins don’t always stay neatly folded. Changes in temperature, changes in acidity, even interactions with other molecules can cause proteins to change their shape.

If a protein unfolds completely and stays that way, it is essentially dead and cannot perform its function in the cell. (This is, quite literally, what happens when you cook an egg. Egg white is a protein called ovalbumin, and when it is unfolded, it goes from being clear and runny to being white and stiff.) Though we eat and digest many denatured proteins, allowing the subunits they are made of to be recycled, within the cell, proteins that are even partially unfolded are essentially useless.

Normally, unfolded or misfolded proteins are degraded and destroyed by the clean-up organelles of the cell.

In Alzheimer’s disease, misfolded proteins persist

However, in Alzheimer’s disease, beta-amyloid protein and the protein tau adopt abnormal misfolded shapes, and the cell is unable to degrade them properly.  Beta-amyloid is the main component of the senile plaques found in Alzheimer brain. Tau protein produces tangles inside the neurons.

Both beta-amyloid protein and tau protein are targeted by drug developers. In future posts, I’ll write about the approaches being used to fight their deposition in brain.

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If you’d prefer some lighter reading, try my Transitions blog.

Wishing you the best,


New Drugs for Alzheimer’s: The Energy Connection

Last Friday, I discussed drugs that treat the synaptic dysfunction of Alzheimer’s Disease (AD). This week we will look at drugs that aim to safeguard brain neurons by protecting their energy supply. These drugs affect the function of organelles within the cell called mitochondria.

If you remember mitochondria from past Biology classes, the phrase “powerhouse of the cell” may come to mind. The function of mitochondria is to produce ATP molecules, which the cell uses as a form of stored energy.

ATP stands for adenosine-tri-phosphate—basically an adenine nucleotide with three phosphate groups attached. The phosphate groups are highly positively charged. To push three positive phosphate groups together takes a lot of energy, because objects of the same charge repel one another. So energy is used to form the bonds holding ATP together, and can be released by breaking, or cleaving, the bond holding the third phosphate in place.

When neuronal mitochondria become less effective producers of ATP, neurons don’t have the energy they need for metabolism, repair, and signaling. If mitochondrial function is badly impaired, neurons die.

Looking for drugs that protect organelle function is a new approach to treating Alzheimer’s Disease, but it makes sense. Mitochondria dysfunction occurs early in AD and promotes synaptic damage as well as neurodegeneration. Furthermore, amyloid proteins can interact with the mitochondria to cause even more impairment in the brain.

When researchers began to study mitochondria in AD, they found that some drugs already in use (Donepezil and Memantine) helped preserve mitochondial structure and enhanced mitochondrial function. How much of their effectiveness in AD is due to mitochondrial protection and how much to receptor blockade is not yet clear.

One new drug that enhances mitochondrial function is currently being tested on AD patients. Thus far it appears that this drug, Latrepirdine, is effective and improves overall well-being in people with AD.

Related articles: Alzheimer’s Disease: physical changes in AD brain. Alzheimer’s Disease: biochemical changes in AD brain. Finding new drugs for the AD brain.

Finding new drugs for the Alzheimer’s brain

Some great drugs have been found by accident. We’ve all heard the story of moldy bread leading to the discovery of pennicillin. But usually, drug discovery is an intentional process. So where does a scientist start?

Three Problem Areas In Alzhimer’s Disease

You have to begin by looking at the disorder you hope to treat and asking, “What are the major problems here?” In Alzheimer’s Disease, the three most obvious problems are:  1) Synapses stop working properly. 2) Cells lack energy. 3) Proteins are misfolded.

Today we’ll look at how scientists target synaptic performance.

Synapses Stop Working Properly

A synapse is the point of communication between two neurons. Here is a picture of two neurons grown in the lab. A synapse between them is circled.

It is at the synapse that messages pass from one neuron to the next. Although the messages that  make up our thoughts and perceptions travel through the neuron as electrical impulses, when they reach the point of passage from one neuron to the next (the synaptic cleft) they move across as chemicals, neurotransmitters. Neurotransmitters drift across the synaptic cleft by diffusion.

It’s as if you were to race across town in one speeding car, then stroll leisurely to another, only to get in and take off once again at breakneck speeds. The electrical impulses travel… well, like lightning. But at the synapse, neurotransmitters gently diffuse across. On the far side of the synaptic cleft, the neurotransmitters interact with receptor molecules and the electrical impulses produced by that interaction race off to the next synapse.

The problems with AD that are most approachable in terms of drug development are at the synapse itself, and are involved with the neurotransmitters and their receptor molecules. Here is a screen capture of a diagram of a normal synapse:

You see the vesicles containing neurotransmitter in the axon terminal (left) and the receptor molecules on the dendritic spine (right). What is not shown in this diagram is a mechanism for clearing neurotransmitter out of the cleft. All synapses have some way of doing this, because otherwise the neurotransmitter chemical would just hang around stimulating the receptors and overexciting the next neuron in line. It would be like you turned on the radio and the volume kept automatically increasing. Really annoying if you can hear well, but not such a bad idea if you’re a little deaf.

In AD, where many neurotransmitter levels are decreased, this is not a bad thing. Many drugs being developed for AD are designed to increase the signal sent through the cleft by intentionally blocking the clearance mechanisms in order to make the signals stronger. Blocking clearance has the same effect as increasing the amount of neurotransmitter available.  Rivastigmine (sold as Exelon) and Galantamine (numerous trade names) work this way, by blocking clearance of acetylcholine from the synapse.

Another drug, Memantine (Namenda), blocks NMDA receptors for the neurotransmitter glutamate.  NMDA receptors are one of six varieties of glutamate receptors, and though they are important in normal brain function, if they are overstimulated, they can actually kill neurons. Blocking the NMDA glutamate receptors, while leaving the other glutamate receptors alone, seems to improve function in many Alzheimer patients. The Alzheimer Reading Room recently ran a post on Memantine research.

Many other drugs in development act on synapses is ways similar to these three. Someday, researchers hope to give physicians a broader choice of remedies for synaptic problems than are available now.

Other posts related to this one:             Alzheimer’s disease: biochemical changes in AD brain             Neurons: you know you’ve got them, but what are they really?            Alzheimer’s disease: physical changes in AD brain            Brain Basics: a look at normal brain

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