Drugs Used in Alzheimer Disease
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Drugs used in Alzheimer disease The causes and symptoms of Alzheimer’s disease (AD) According to the definition of the International Classification of Diseases (ICD-10), dementia - a complex of symptoms of pluricausal etiology. It is caused by brain disease and is usually chronic and progressive. In AD such higher cortical functions as memory, thinking, understanding, ability to learn and speak, perception of time and space as well as the ability to care for oneself are impaired. 1 Drugs used in Alzheimer disease The damage of cognitive functions is accompanied by diminished emotional control, dysfunctional social behaviour and decreased motivation. Consciousness is not affected in dementia states. An increased number of dementia states and depression syndromes are observed in people above the age of 65. The number of dementia cases increases in geometric progression and doubles every 5 years. About 350 000 people suffer from Alzheimer’s disease in Poland and about 25 mln worldwide. 2 Drugs used in Alzheimer disease A person’s age and a history of dementia in his or her family are considered to be hazard factors related to Alzheimer’s disease. Women are observed to be affected by Alzheimer’s disease more often than men. However this is not a result of sex differences but a reflection of the fact that women live longer. Less educated people seem to be affected more often and more severely. Between 10% and 15% of cases of AD are of genetic origin. 3 Drugs used in Alzheimer disease At present the following classification of AD cases is used: early-onset Alzheimer’s disease (affecting individuals aged below 60-65) late-onset Alzheimer’s disease. Early-onset AD has a familial nature and many mutations that cause this kind of disorder are known. They are observed in: the gene encoding amyloid precursor protein, located on chromosome 21 the gene of presenilin 1, located on chromosome 14 the gene of presenilin 2, located on chromosome 1. In the case of late-onset AD, the presence of the gene encoding apolipoprotein E4 is considered the main genetic factor. 4 Drugs used in Alzheimer disease The many somatic causes of AD include among others: metabolic diseases – hypothyreosis, diabetes, arterial hypertension toxic causes – alcohol, metal intoxication, chemical compounds and drugs. 5 Drugs used in Alzheimer disease The amyloid precursor protein (APP) is situated in the cell membrane. The sequence of beta-amyloid (the word beta means, that the protein is concertina- shaped, also called a pleated sheet) consists of 40 to 43 rests of amino acid. The point mutations of the APP gene are responsible for some forms of familial AD. 6 Drugs used in Alzheimer disease Different secretases participate in the transformation of APP. -Secretase cleaves -amyloid between the 16th and 17th amino acid, thus preventing the creation of -amyloid 40/42 and its deposition in the brain. The extracellular domain APPs that is cut off has very important neurotrophic and neuroprotective properties. APPS especially stabilizes the homeostasis of calcium ions in neurons and protects neurons from being over-stimulated by the stimulating transmitter, glutamic acid. 7 Drugs used in Alzheimer disease An alternative transformation caused by -secretase leads to the formation of -amyloid. -Secretase, which cuts the extracellular part of APP, leaves the whole sequence of -amyloid near the C-end fragment of protein. Next, -secretase releases - amyloid. 8 Drugs used in Alzheimer disease Under normal conditions the main created peptide is soluble -amyloid (A1-40); only approx. 10% of A are peptides A1-42 and A1-43. -Amyloid acts neurotoxically only in fibrous form. The longer the chain of A, the greater its ability to aggregate. One of the known mutations causes an equal increase in the biosynthesis of both forms of amyloid, A40 and A42, another leads to the appearance of the easily precipitated A 42. This fibrogenous -amyloid plays an important role in creating senile plaques, but it isn’t the only factor responsible for their creation. 9 Drugs used in Alzheimer disease -Amyloid acts neurotoxically, because it induces the creation of free radicals and impairs the transport of glucose in neurons, which leads to the damage and death of cells. 10 Drugs used in Alzheimer disease Presenilins are built from amino acids and permeate the cell membrane many Lumen of a tubule times, creating loops that Membrane of Golgi protrude outside and inside apparatus the membrane. If presenilins are to be active they have to be cut inside one of these loops by an enzyme, presenilinase. Presenilins modulate the metabolism of -APP in such a way that they behave like gamma- Cytoplasm secretase, thus controlling the length of A. 11 Drugs used in Alzheimer disease Presenilins play an important role in regulating the level of calcium, in moving proteins in cells and in the neuron membrane as well as in differentiation of nerve cells and in apoptosis. Mutations of the genes of presenilins 1 and 2 lead to the onset of AD very early on, even before age 30. Mutations within the code gene of APP and the code genes of presenilins also increase the production of -amyloid A42. The genes of presenilins 1 and 2, similarly to the gene of APP, are causative genes because any changes in them cause AD. 12 Drugs used in Alzheimer disease Apolipoprotein E appears in large amounts in nervous tissues and plays a vital role in the functioning of the peripheral and central nervous systems. It is produced predominantly in astrocytes and carried by low-density lipoprotein into neurons. Apolipoprotein E is a serum protein which takes part in the transport of cholesterol. The gene of ApoE occurs in chromosome 21 in three variants – E2, E3 and E4. The isoform ApoE2 demonstrates protective action but ApoE4 increases the risk of developing AD. In people with AD ApoE4 is most often observed. Individuals who have inherited the gene of apoE4 in both chromosomes are 8 times more likely to suffer from AD and the disease can appear at a younger age. In 50 per cent of patients with late-onset FAD (familial-Alzheimer’s disease) alleles ApoE-4 are observed on the long arm of chromosome 21 (16% in the control group). In 40 per cent of persons with sporadic Alzheimer’s disease (SAD) such location of these alleles is observed. 13 Drugs used in Alzheimer disease Apolipoprotein E: increases accumulation of -amyloid in neurofibrillary structures is an important AD risk factor is not solely responsible for the onset of AD is not a specific AD factor The gene of apolipoprotein E is recognized as a risk gene, because the presence of this gene increases the AD risk factor but it does not mean the certainty that AD will appear. 14 Drugs used in Alzheimer disease Hyperphosphorylated tau proteins are the next factor causing the atrophy of neurons. These proteins are coded on chromosome 17. In physiological state, tau protein is one of the proteins which stabilize microtubules. In Alzheimer’s disease tau proteins form paired helical filaments and neurofibrillary tangles which surround the cores of senile plaques. Senile plaques consist of -amyloid, apolipoprotein E and other proteins. Senile plaques accumulate in intracellular spaces and are accompanied by the cells of inflammatory reaction, called microglia. Microglial cells are cerebral analoqus of macrophages. They try to decompose and Damaged microtubules remove damaged neurons and, possibly, senile plaques. 15 Drugs used in Alzheimer disease In Alzheimer patients the following is observed: decreasing number of neurons (by up to about 80%), especially those whose neurotransmitters are acetylocholine and glutamic acid; in these regions of the brain the plicate are becomes smooth diminishing mass of the whole brain by about 10-15% compared with a healthy person at the same age diminishing area of the hippocampus, which is responsible for memory processes diminishing cerebral cortex, especially its front part by about 30%; the cerebral cortex participates in reasoning and other important processes. 16 Drugs used in Alzheimer disease Morphologic changes are accompanied by biochemical changes: increased concentration of apolipoprotein E in plasma and cerebrospinal fluid decreased choline acetyltransferaze in the cerebral cortex and the hippocampus, by about 70%, which results in a decreased concentration of ACh decreased glucose metabolism in the cells of the temporal lobes of the cerebral cortex, by above 40%. 17 Drugs used in Alzheimer disease The beginning of Alzheimer’s disease is difficult to discern. A person’s memory is slightly worsening and his or her work is becoming less efficient in spite of a significant effort. Such symptoms can accompany different diseases and result from exhaustion or stress. In the further stages of the disease memory defects are compounded by difficulty in remembering new facts and an inability to concentrate. Changes like those are also typical of the normal process of ageing. Although they are troublesome they don’t eliminate an Alzheimer person from social life. 18 Drugs used in Alzheimer disease The next stage of the disease is called dementia. More and more serious memory lapses occur. A sick person loses his or her sense of time and space and is often lost in what used to be familiar surroundings and unable to find the way home. Next, close relatives are no longer recognised, conversation becomes impossible and difficulty in getting dressed is observed. All those problems are accompanied by psychical changes such as frequent mood swings from aggression to apathy. In the final stage of AD, the patient’s consciousness is affected and the ability to move disappears. The person cannot stay upright or control his or her bodily functions. 19 Drugs used in Alzheimer disease Those changes, over a period of 5 years, make the sick person totally dependent on the care of other people.