In the News: Alzheimer’s Disease cause identified? In Nature: January 8, 2004

Alzheimer’s is a disease that affects between 8 – 15 million people worldwide^{2 4} and this level is expected to grow as the global population continues to age. Although the cause of Alzheimer’s is not known, research is getting much closer to resolving this mystery. A protein known as beta amyloid is known to cause the plaques that are seen in advanced Alzheimer’s, but are these plaques the cause or effect of the disease?

Alzheimer’s is a brain degenerative disease that causes irreversible damage. Patients who are diagnosed with probable Alzheimer’s may live for another 8 – 10 years. Absolute diagnosis is not known until after the patient is deceased and brain tissues are examined. However a multitude of new techniques have greatly improved the accuracy of diagnosis in early stages of Alzheimer’s.

Exactly when the disease starts is not known, however symptoms do exist as a person ages. Alzheimer’s is the most common cause of dementia in people over 65³, with incidents doubling every 5 years after this age. Dementia is a term used to describe a group of symptoms such as lack of emotion, memory problems, and inability to complete a simple task. These symptoms are caused by a change in brain function, which may be a result of many different conditions. Some changes in the brain are reversible and others like Alzheimer’s are not reversible¹. A very important point is that Alzheimer’s is not a normal part of aging.

Alzheimer’s causes a breakdown in the connections between nerve cells, known as neurons, and causes many of these cells to die. Alzheimer’s disease starts slowly with forgetfulness and difficulty in solving simple math problems. The disease progresses to problems in accomplishing simple tasks, for example combing one’s hair. A person’s thought process is clouded, and problems in speaking, reading, writing, and understanding become increasingly apparent. Personality and behavioral changes may also occur. In later stages, an inflicted person becomes in need of total care¹.

Two main features prevail in Alzheimer’s. One feature is the formation of beta amyloid plaques in greater abundance than during normal aging. The second is build up of neurofibrillary tangles within the neurons. These tangles are made up of a protein called tau. Normal tau stabilizes the neuron’s support structure, but in Alzheimer’s, the tau protein is chemically changed so it pairs together and forms tangles. This change results in communication problems between neurons and eventually death of the neuron cell. Abnormally high plaques levels of beta amyloid fragments and tau protein occur predominantly in the hippocampus and the cerebral cortex regions of the brain. Short term memory and the ability to learn is affected in the hippocampus region^{3 5}. The cerebral cortex controls thinking, learning, speaking, memory, and decision making processes⁵.

	Within the brain, Amyloid Precursor Protein (APP) helps neurons to grow and survive, and may help neurons repair themselves5. Proteins called enzymes act as scissors that cut substances in very specific places. Two enzymes, beta secretase and gamma secretase, cut APP resulting in fragments. Some of these fragments are known as beta amyloid fragments. These beta amyloid fragments combine together with other substances to form insoluble plaques 3 5. These plaques have both physical and chemical affects on the neuron membrane to which they attach. This attachment is proposed by some scientists have a disrupting effect on the neuron cells function6.
	In the 8th of January 2004 issue of Nature, the journal reported on a scientific study that limited the production and formation of beta amyloid fragments in order to decrease Alzheimer’s symptoms. This was done by producing genetically modified mice that had no beta secretase enzyme to cut APP into beta amyloid fragments. In addition, genetically modified mice were developed that had high levels of APP and had many of the symptoms associated with Alzheimer’s. This later type of mice acts as a model for Alzheimer’s. These two types of genetically modified mice were then bred to each other. Subsequently, their offspring were then bred to each other resulting in offspring that were: Normal mice. Mice that produced abundance of APP (Alzheimer’s model mice). Mice that produced no beta secretase enzyme to cut APP. Mice that had an abundance of APP but no beta secretase enzyme.
	All four types of mice were then tested for their ability to recognize a familiar mouse and for memory function. Mice with an abundance of APP (Alzheimer’s model) had the hardest time recognizing a familiar mouse and had other memory problems. However mice that had the genes for both the Alzheimer’s model and no beta secretase acted like normal mice4. This study may lead to possible treatments for Alzheimer’s by eliminating the enzyme beta secretase4.  In addition, this study addresses issues beyond Alzheimer’s disease. It shows that genetically modified animals can be used in a positive manner to learn about a devastating disease that would not be possible otherwise.

Research on Alzheimer’s disease continues in order to understand the cause of Alzheimer’s, and to develop earlier and better diagnostic techniques that will delay the progression of the disease or prevent it all together. Much has been learned, but the search is not over.

References: Alzheimer’s Disease cause identified? In Nature: January 8, 2004

1. ADEAR. Alzheimer’s disease Education and Referral Center. National Institute of Aging. www.alzheimers.org
2. MdConsult. 2002. Alzheimer’s Disease. Nidus information service. www.mdconsult.com
3. NIA. 2003. Alzheimer’s Disease Progress Report 2001 – 2002. National Institute of Aging. National Institutes of Health NIH Publication#:03 – 5333.
4. Ohno, M, Sametsky, E. A., Younkin, L. H., Oakley, H., Younkin, S. G., Citron, M., Vassar, R and Disterhoft, J. F. 2004. BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer’s disease. Neuron 41 27 – 33.
5. Rodger, A. B. 2002. Alzheimer’s Disease unraveling the mystery. National Institute of Aging. National Institute of Health. NIH Publication No – 02 – 3782.
6. Wood, W. G., Eckert, G. P., Igbavboa, U and Muller, W. E. 2003. Amyloid beta-protein interactions with membranes and cholesterol: causes or casualties of Alzheimer’s Disease. Biochimica et Biophysica Acta 1610, 281 – 290.

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