1.0 Alzheimer disease is known in all over the world. It remains a challenge despite the fact that scientist understand many of the molecular aspects which surround the development of the disease (Beyreuther 2001). Every day we hear in the T.V or read in the newspapers or the internet about this brain disease. But what is Alzheimer disease and why is so difficult and complicate to prevent it or to find therapies for it?
Alzheimer's disease (AD) is characterized by neurodegeneration and changes in cellular processes, including neurogenesis. Proteolytic processing of the amyloid precursor protein (APP) plays a central role in AD.
1.1 Alzheimer disease (AD)
Alzheimer disease (AD) was first described by Alois Alzheimer in 1907, is characterized by disruption of the cytoskeleton of neurons. It is a progressive and serious brain disease. Alzheimer'sÂ destroys brain cells, causing problems that are serious enough in order to affect memory and everyday activities. It is the most common form of dementia (Alzheimer disease accounts for 50 to 70% of dementia cases), a general term for the loss of memory and other intellectual abilities serious enough to interfere with daily life. In most people with AD, symptoms first appear after age 60.Â
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Percentage (%) having the disease.
Figure 1: The Alzheimer disease is a progressive brain disorder that causes a gradual and permanent loss of higher brain functions such as memory, language skills and perception of time and space. As a result people with the disease lose the ability to care for themselves. The situation depends from the age.
The figure shows that as the age increases, the percentage of people with the disease it is also increases.
2.0 Causes of Alzheimer disease.
As it has been known until today the Alzheimer disease is mainly caused by genetic factors but also might be caused from environmental factors and the person's health. The genetic factors will be analyzed in the next parts of the essay, although it is important to mention that if the family history of a person shows a parent with the disease, there are two or three times more chances for the person to have the disease in the future.
Furthermore, if more than one parent or close relatives are affected with the disease, then the possibilities are increased.
By saying environmental factors, we mean that if a person has a history with a head trauma or exposed to toxic conditions, it is possible to have the disease in the future. Moreover, if a person has diabetes mellitus or vascular disease (like heart disease), it is having lots of possibilities in the future to develop the disease.
3.0 Symptoms of the Alzheimer Disease.
3.1Symptoms of AD and the stages that are separated
The symptoms are separate in three stages. In the primary stages of the disease, the patient might discover that it is difficult to find the correct word in a conversation or they are having difficulties to write. Later, those problems become more serious; for example, the person with the disease may have difficulties to remember what day or month it is or become unable to find his/her way around familiar surroundings.
Those people that have the disease do not react with in same way or have the same symptoms at the same time but usually the symptoms progress in three stages: the mild, moderate and severe.
The mild stage is the beginning of the disease and it might last from 2 to 4 years. Persons in that stage easily get lost or forget places. They lose things and they have difficulties to pay bills or to remember things.
The moderate stage is the longest of the three stages. The person with the disease might be in that stage from 2 to 10 years. The person with the disease has clearly become disabled. The symptoms are mainly the same as the previous stage but they become even more serious. For example, the person has difficulties to recognise familiar persons or places. They also have difficulties with their speech, to read or to write.
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The last stage may last from 1 to 3 years. In that stage the people that carry the Alzheimer disease may lose the ability to speak. Moreover, they are not able to recognise people or remember basic things from their life. They are not able to control some of their body functions, for example, swallowing. The people in that stage go to sleep for a lot of the time and the most important; because they are weak from the disease it is easy to become susceptible to other diseases like skin infections and respiratory problems.
Furthermore, as the disease progresses, depression becomes more common- 5-8% of the patients suffer from serious depression with insomnia or anorexia. Moreover, psychotic behavior, delusions and agitation with aggressive behaviour are some of the major symptoms that a patient develops. Most Alzheimer patients die of complications such as pneumonia. One of the first visible symptoms is the memory loss, which can be quite mild in the first stages of the disease. It usually begins with some difficulty in recalling people's names, telephone numbers or remembering the details of events or conversations during the day.
Examples of Mild stage
Examples of Severe stage
Memory loss and confusion.
Difficulty in recognizing people in their family or close relatives and friends.
Taking longer to complete normal everyday jobs.
Difficulties in working with numbers.
Difficulties to communicate.
Confusion about the location of familiar places.
Skin infections, difficulties in swallowing.
Figure 2: The figure shows some other examples of symptoms in a patient with the Alzheimer disease in the first and in the last stages of the disease.
3.2Early and late onset Alzheimer:
Most cases of the Alzheimer disease occur in people that are over 65 years old and are referred to as late-onset Alzheimer. On the other hand, the disease could affect people that are between 30 and 50 years old, although it is not very frequent (only 2% of the Alzheimer cases are early onset) and is named early-onset Alzheimer. It is important to say that the symptoms in both types are identical.
The typical length of time between the appearance of the first symptoms of the disease and the death seems to vary from 4 to 16 years. It is proved that women with the disease generally survive longer than men (Debra et al, 2006).
4.0 GENETIC CAUSES OF THE DISEASE
The Alzheimer disease develops when a complex series of actions in the brain gradually make nerve cells in the brain stop working and die. Age is the most important risk factor for Alzheimer disease.
The genetics of the Alzheimer disease seems to be difficult to understand it and it is controversial.
Molecular genetics studies in pedigrees, using a pattern of an autosomal- dominant single gene, revealed that four different genes are connected with inherited susceptibility to Alzheimer disease.
4.2 The role of plaques and tangles:
The main pathologic hallmarks of AD are neuritic plaques and neurofibrillary tangles which are involved in the process leading to progressive neuronal degeneration and death. Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. Plaques are extracellular deposits, consisting primarily of the amyloid beta (A-beta) peptide. This 39- to-43 amino acid peptide is proteolytically created from a high molecular weight precursor protein called amyloid precursor protein (APP). In contrast to the form with 40 amino acids (AÎ²40), the variant with 42 amino acids (AÎ²42) is thought to be the pathogenic form triggering the pathological cascade in AD. Since this peptide is cleaved from amyloid precursor protein (APP), interest in APP isoforms is great and a rapid method for detection of the presence of each isoform and would be a huge advantage in research on determination and concentration measurement in both the diseased and non-diseased states ( Bohrmann et al. 2006).
4.3 But how we do Isolate disease genes?
There are two common approaches in order to isolate those genes that carry the disease. The first strategy is to clone a "candidate gene", whose role in the disease is based on its biochemical function that is associated with known biochemical phenotypes which are connected with the Alzheimer disease.
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The second strategy to isolate those genes that it carry the AD is more complex than the first one. Basically is based on efforts to recognize the chromosomal location of the disease gene and then, to isolate the gene from this chromosomal position. Therefore, the identification of the chromosomal location can be achieved through genetic linkage studies. These studies use polymorphic chromosomal markers in order to show co-segregation of the disease trait with a group of markers whose chromosomal location is already known. In addition, as soon as the location is defined, the identification of possible candidate genes that have previously been mapped on that chromosomal area can be done. It is important to mention that many times the chromosomal area that is defined encloses unknown genes or genes that, although they have previously been mapped in the specific region, do not seem to be connected with the disease. In that case, extra novel candidate genes can be isolated from the genomic DNA in the chromosomal area. This can be done in two ways. The first one is "exon trapping" and the second one is "gene tracking" (Tanzi et al, 1997).
4.4 MUTATIONS IN FOUR GENES ARE CONNECTED WITH EARLY ONSET Alzheimer Disease.
Research has found that a common polymorphism of Î±2 macroglobulin is connected with an important increase of the risk for a person to develop late onset Alzheimer disease. Researchers discover that missense mutations in three genes apparently cause an autosomal dominant form of early onset Alzheimer disease. These genes are the amyloid precursor protein gene that is found in the chromosome 21, and genes of preselinin 1 and preselinin 2 that are located on chromosomes 14 and 1, correspondingly.
The first gene identified that is connected with the inherited susceptibility to AD is the amyloid precursor protein gene.
Amyloid is an extracellular mass of amyloid fibrils. Those fibrils have a diameter of 7-10 mm. In the brain, amyloids include amyloid Î² protein (AÎ²) and they are connected with proteins such as Î±1 antichymotrypsins, apolipoprotein E and J, vibronectin and non AÎ² component.
Studies that have taken place about these missense mutations support the "amyloid cascade hypothesis" of Alzheimer disease. The amyloid ancestor protein mutations code for amino acids at or even close to areas, where the precursor is enzymatically cleaved. As a result, we have the creation of slightly longer forms of Î² amyloid being out of sight. In addition, these easily transform in to highly unsolvable amyloid fibrils which form the main part of the senile plaques. Senile plaques are extracellular deposit of amyloid in the gray matter of the brain. Analogous changes with the Î² amyloid production seem to take place in the mutations that are connected with the Alzheimer disease in presenilins 1 and 2 (Tanzi et al, 1997).
Figure 3: Schematic representation of APP gene and its three major isoforms. The human APP gene contains 19 exons. Alternative splicing produces the three major isoforms shown. AÎ² is derived from parts of exons 16 and 17.
After it was found that Î²APP missense mutations were not very often present as a cause of the AD, other studies, took place. In contrast with the previous studies the remaining non-sex linked chromosomes except 19 and 21, were used. The result of those studies was the discovery of a number of polymorphic genetic markers on chromosome 14q24.3 (D14S43, D14S71, D14S77 and D14S53) that were strongly connected with an early onset form of AD.
Studying the presenilin proteins, we observe that they are homologous with numerous membrane-spanning domains. This allows them to behave as chaperone molecules during the dealing out of the amyloid precursor protein, enlightening the sides in the molecule to enzymatic cleavage.
Those mutations that are associated with amyloid precursor proteins are tremendously rare, in contrast with the mutations that are connected with presenilin 1 which are found in half or even more of the cases of early onset Alzheimer disease (Tanzi et al, 1997).
Through the cloning of the presenilin 1 gene on chromosome 14, what was found in the public nucleotide sequence databases, was a sequence that was related to the sequence of the P1 gene. Research discovered this similar sequence was a result of a gene on chromosome 1. This gene encodes a polypeptide whose open reading frame has 448 amino acids. Moreover, further mutational studies revealed two different mutations in the presenilin 2 gene, separating early onset forms of Alzheimer disease.
A difference between the mutations of presenilin 2 and the mutations of Î²APP and presenilin 1 genes is derived if we analyse the phenotypes. The phenotype that is connected with Presenilin 2 mutations is more variable in contrast with the phenotype in the other two cases. Thus, while the greater part of heterozygous transporters of missense mutations in the Î²APP gene develops the disease between the ages of 45 and 65 years and for Presenilin 1 gene between the ages of 35 and 65, in the case of Presenilin 2 they develop the disease between the ages of 40 and 85 years (Tanzi et al, 1997).
The APOE gene is associated with the familiar risk factor. Moreover the apolipoprotein e4 allele on chromosome 19 is connected with a higher risk for late onset Alzheimer disease.
Structure and function
The APOE protein has 299 amino acids that are cleaved from a single peptide as it is secreted from the cell. Two large domains create the APOE. The first one is an amino -terminal domain that cooperates with the APOE receptors and the second one is a carboxy-terminal domain that interacts with the lipoprotein elements. Both domains are joined by a hinge region.
The APOE gene in humans contains three common polymorphisms. The most known one shows the presence of cysteine at codon 112 and it is found in 75 % of Caucasians. The second polymorphism the Îµ4 is found at codon 112 and reflects the replacement of arginine for cysteine (15% of Caucasians). Finally, the third variant, the Îµ2, contains cysteine at codons 112 and 158 (found in 10% of Caucasians).
In addition, studies that have been done on these polymorphisms using normal populations as controls and comparing them with people with the disease proved that the levels of the Îµ4 allele increased in about 40% of the patients. Moreover, the levels of the Îµ2 allele also increased in a smaller frequency (around 2%).
The connection of the Îµ4 allele with the disease was also proved with more studies during years and by using people from different countries from all over the world.
The connection of the AD with the Îµ2 allele is less clear, especially at younger ages.
But how does APOE involves with the Alzheimer disease?
The APOE including lipoproteins that are essential for the avoidance of neurodegeneration. Therefore, APOE is not able to support neuronal survival if the conditions are toxic.
APOE cooperate with Î¤ and microtubules. APOe4 is not able to protect Î¤ from aggregation into neurofibrillary tangles.
Finally, APOE cooperate with AÎ² or APP in order to promote the formation of AÎ² aggregates. Furthermore, it get involve in clearance (Tanzi et al, 1997).
CLU, CR1 AND PICALM GENES
Recently, three new genes, except APOE4, were found to be connected with the Alzheimer disease. The discovery of these genes makes the scientists more optimistic that they will understand better the Alzheimer disease during the years.
The CLU gene encodes a protein that is called clusterin. This protein normally is responsible for the brains protection in a lot of different ways. Some variations that may happen in CLU can remove the productive benefit of clusterin and lead to Alzheimer (which includes the development of amyloid protein plaques around the brain cells).
The PICALM gene affects synapses. Synapses are connections between the cells of the brain and they play an important role in the transportation of the molecules to or even inside the nerve cells. This helps the brain to form memories and other major brain functions. Therefore, the health of synapses is connected with the memory situation in the Alzheimer disease; in addition, if changes that happen in the genes affect the synapses, then the diseases development will also be affected.
It is important to mention that the effect of these genes is smaller than the effect of APOE4 (of which the amount of risk is 19-20%, in contrast with these genes, which is around 10%).
4.9 Can a vaccine cured the disease and how?
During experiments a vaccine was discovered that cleared the amyloid plaques in the first stages of the disease. The disadvantage of that particular vaccine was that did not have any significant effect on dementia. However, scientists believed maybe non plaque AÎ² ologomers are the first pathogenic form of AÎ². Therefore, toxic oligomers that are also known and as Amyloid-Derived Diffusible Ligants (ADDLS), are bound to a surface receptor on neurons and as a result the structure of the synapse is changed.
Thus, neurons cannot communicate between them.
A possible receptor for the AÎ² oligomers could be the Prior Protein, which is the protein that has been connected with Creutzfeldt-Jakob and Mad Cow diseases. In addition it could be possible also to be associated with the Alzheimer disease because if we compare the mechanisms of those neurodegenerative disorders there are many similarities.
4.10 How are estrogens connected with Alzheimer disease?
Studies revealed that estrogen can help to stop or delay the disease. Scientists found that postmenopausal women who used estrogen for a year delayed or even reduced the risk of developing the disease. Moreover, Dr Toran Allerant in 1970 proved that estrogen encourages the increase of axons and dendrites in cultured slices of the brain.
Alzheimer's disease therapy is still an important challenge. Is a very complex and complicated disease and both conventional and unconventional strategies are characterized by side effects that heavily impair pharmacological success.
Human reproductive cloning
The first way that may help scientists to discover a treatment for the disease is "human reproductive cloning". This makes it possible to create perfect copies of ourselves. This method is very useful but when scientists used it on animals the cloned animals had a high frequency of cancer, arthritis or other diseases.
Researchers can use "therapeutic cloning"; for example, if we clone a new liver from a person's own DNA, the possibilities that the body will reject it are reduced. So, this can be done in the case of Alzheimer- maybe a new brain can be cloned by using patients DNA.
In the future, with studies we must find out how to deactivate the genes that are responsible for rejecting the transplanted organs. The studies take place on pigs because their tissues and organs are very similar to human tissues and organs. The process of growing an organ in one species in order to use it in humans is known as "xenotransplantation".
In the future, more studies should take place in order to understand better why cells die in Alzheimer disease. Specifically we have to understand completely the mechanism of cell death. The main difficulty that must be resolved is that models that involve amyloid deposition do not have a small number of cells that have died in order to investigate them. By saying models, we mean transgenics with mutant human AÎ²PP genes.
It is important to understand better these mechanisms because they are responsible for abnormalities like tan conformation and phosphorylation and amyloid Î² deposition. The human tan transgenic mice give us this chance to study those mechanisms of cell death.
In the future efforts should be made in order to make the vaccine that has already been discovered and that can reduce the amount of beta amyloid plaques in the brain, and as it can improve the way that mice perform a memory test,it should be able to be used in people. This has been rejected because of the side effects.
Scientists should try to find out exactly how plaques and tangles are related with the disease. They believe that they somehow block the nerve cells. In addition, cells cannot communicate between themselves because they lose this ability and finally cannot survive. In my opinion, more studies should be done in the future in order to make sure that this hypothesis is correct.
Ways through the discovery of vaccines should be found in order to imitate the symptoms of the disease or repealing the damage already done in the brains of those people that have already had the disease.
Alzheimer's disease therapy is still an important challenge. Both conventional and unconventional strategies are characterized by side effects that heavily impair pharmacological success. In the future the possibilities therapies to find are many because of the fact that research are in a high level. Who knows maybe in the future scientists be able to cure and those people that they already have the disease and not only found threatments in order to prevent the disease.