Finding new drugs for the AD 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

If you have comments or a question, please leave a Reply.

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2 thoughts on “Finding new drugs for the AD brain

  1. Pingback: New Drugs for Alzheimer’s: The Energy Connection | by Susan Craig Ideas, Information, Insight

  2. Pingback: Developing new drugs for Alzheimer’s Disease: Targeting misfolded proteins | by Susan Craig Ideas, Information, Insight

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