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Alzheimer's disease abstract
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13
FEDERAL AGENCY FOR EDUCATION OF THE RUSSIAN FEDERATION
Federal State Educational Institution of Higher Professional Education "Altai State University"
Faculty of Biology
Department of Human and Animal Physiology
ALZHEIMER'S DISEASE
(summary)
Barnaul 2006
Content
Introduction 3 1.
Etiology of the disease 4 1.1 Pathogenesis.
Mechanisms of genetic predisposition 4 1.2 Biochemistry and morphology of disease development 8 2.
Clinical manifestations 13 Conclusion 15 References 16
Introduction
To date, a number of neurodegenerative diseases have been described, which are characterized by a gradually developing destruction of various brain structures caused by the mass death of neuronal and / or glial cells, which is accompanied by a significant violation of all aspects of the central nervous system.
Among such diseases, Alzheimer's disease (AD) deserves great attention.
The disease was described in 1906 by the histologist Alois Alzheimer and later named after him.
According to American researchers, in the United States, AD occurs in 2.0-2.5% of the population under the age of 70 years, in older age groups, the frequency of the disease increases approximately twice every five years.
In our country, a large number of elderly people also have AD.
Thus, according to the Center for Mental Health of the Russian Academy of Medical Sciences, up to 4.5-5.0% of the population of Moscow aged 60-65 years suffer from Alzheimer's type dementia.
The disease affects people of all races and ethnic groups; there are slightly more women than men among the patients, although this may be due to the longer life expectancy of women [1].
1. Etiology of the disease
Most cases of AD have a multifactorial nature and are sporadic.
At the same time, numerous population studies have shown that 25-40% of cases of AD can be familial, i.e. there is at least one more patient with this disease in the proband family.
The important role of genetic factors in the development of AD is confirmed by the high concordance of the disease among monozygotic twins.
The analysis of a large number of families with AD allowed us to establish a bimodal distribution of the values of the age of onset of symptoms, and the conditional boundary between early and late family cases of the disease is considered to be the age of 58 years.
In early cases of familial AD, the disease is usually inherited as an autosomal dominant trait associated with damage to one main gene.
Late family cases of AD are heterogeneous; most often in these cases there is a polygenically determined predisposition to AD, in which the accumulation of repeated cases of the disease among relatives is associated with the action of a complex of genetic and environmental factors common to members of this family.
According to some estimates, hereditary monogenic forms account for about 5-10% of AD cases in general [2].
1.1 Pathogenesis.
Mechanisms of genetic predisposition
To date, it has been established that AD is caused by mutations in 4 genes located on chromosomes 1, 14, 19 and 21 (Table.1) [1].
3 genes have been identified, mutations of which lead to the development of hereditary (autosomal dominant) forms of AD with early onset of symptoms.
One of them is the gene of the amyloid precursor protein, localized on chromosome 21q 21 and designated by the abbreviation ARP (from the English Amyloid Precursor Protein).
The gene consists of 19 exons, and the amino acid sequence in amyloid is encoded by part of exons 16 and 17; this amino acid sequence is located in the carboxyl part of the ARP protein.
Normally, the ARP protein undergoes proteolysis under the influence of b -, b and g secretases; the last two proteolytic pathways lead to the release of intact b amyloid molecules, which in itself is not accompanied by the development of the disease.
All eight known pathogenic point mutations of ARP are located in the 16 and 17 exons of the gene and lead to a violation of the b - and g secretase processing of the ARP protein product, resulting in hypersecretion of the amyloid peptide b or preferential secretion of longer forms of amyloid that are prone to rapid fibrillar aggregation.
In both cases, the released peptide acquires amyloidogenic properties - the process underlying the formation of senile plaques in the brain parenchyma.
In general, mutations in the ARP gene are very rare: they are detected in only 20 families worldwide and, according to approximate estimates, cause no more than 5% of all cases of familial AD with early onset of symptoms.
Two other genes that cause the majority of cases of early familial AD and are located on chromosomes 14q24.3.
and 1q31-42, were cloned in 1995.
These genes are highly homologous and encode related membrane proteins presenilins (presenilin 1 (PS1) and presenilin 2 (PS2), respectively).
In the brain, presenilins are expressed mainly in neurons and are localized in the EPR of the bodies of neurons and their dendrites.
It is assumed that one of the functions of presenilins may be associated with the regulation of intracellular transport of membrane proteins, including the precursor protein of amyloid.
Mutations in the presenilin genes are accompanied by hyperproduction of amyloidogenic forms of the peptide b amyloid, which form senile plaques.
This phenomenon is most likely due to the activation of the secretase proteolysis of the APP under the conditions of "delay" of this protein in the EPR.
Another possible mechanism of the pathogenic effect of mutant presenilins may be the induction of apoptosis due to impaired regulation of calcium homeostasis in the EPR and activation of free radical reactions.
In this case, the detected violation of the processing of ARP in cells expressing mutant presenilins is secondary in relation to the implemented "apoptic cascade".
In general, slightly more than half of all familial cases of AD with early onset are caused by mutations in the presenilin genes; the majority of cases are associated with presenilin 1, while damage to the presenilin 2 gene is very rare (only 3 described mutations).
It should be emphasized that 70% of all known mutations in the presenilin genes are unique (i.e., each of them was detected only in one family).
Most mutations in the genes of ARP and presenilins are characterized by complete penetrance by the end of the 6th decade of life and inevitably lead to the manifestation of the disease, provided that the mutation carrier reaches the appropriate age.
The analysis of clinical and genetic correlations showed the absence of any significant differences between the phenotypes of individual molecular forms of AD, with the exception of the age range of the appearance of the first symptoms of the disease.
When the ARP gene is damaged, the disease manifests at the age of 39-67 years, a slightly later onset of the disease is observed in patients with mutations in the presenilin 2 gene(50-65 years), whereas in the case of mutations in the presenilin 1 gene, it is the most aggressive and early (the onset of the disease is from 24 to 56 years).
Some mutations in the presenilin 1 gene can in isolated cases cause the development of an atypical BA phenotype characterized by a combination of early dementia with lower spastic paraparesis.
In a significant number of families with early AD, mutations in the genes of ARP and presenilins were excluded, which indicates further genetic heterogeneity of the early form of the disease.
A classic example of a pronounced genetic association is the importance of apolipoprotein E as the most important endogenous risk factor in the development of a late form of AD.
Apolipoprotein E (apoE) is a protein with a molecular weight of 34 kDa, encoded by a gene on chromosome 19q13.
2. ApoE plays a key role in the metabolism of lipids (especially cholesterol), contributing to their redistribution between cells of various organs.
In 1993, it was established that apoE is one of the proteins that specifically bind to amyloid b.
The apoE gene has 3 main alleles (e2, e3 and e4), which differ by single nucleotide substitutions and determine the existence of 3 isoforms of the apoE protein, and the e3 allele is the most common in the general population.
In a series of studies conducted in 1993-1996, it was found that the e4 allele of the apoE gene is significantly more common in patients with late AD - both familial (50%) and sporadic (40%).
Moreover, the risk of developing AD throughout life, depending on the apoE genotype, is dose dependent: in homozygous carriers of the e4 allele, it is the highest and is about 90%, in heterozygous carriers of e4, it is 47%, while only 20% of people without the e4 allele develop AD in old age.
The dose of the "unfavorable" e4 allele also directly correlates with the intensity of the formation of amyloid plaques in the brain of patients with AD [2].
Table 1.
Genes associated with Alzheimer's disease [1]
Genes
Manifestation of the disease*, type
Protein is a product of a gene
Localization of the gene
AD 1
Early, inherited
ARR
21q.21.2
AD2
Later, inherited sporadic
ApoE
19q.13.2
AD3
Early, inherited
Presenilin 1
14q.24.3
AD4
Early, inherited
Presenilin 2
1q.24.3
* Early manifestation of the disease before 65, later after 65 years.
1.2 Biochemistry and morphology of the disease development
When examining the brain of deceased patients, atrophy is revealed, especially pronounced in the associative zones of the neocortex, hippocapal and parahippocapal structures, along with a noticeable expansion of the lateral ventricles.
The most significant, "marker" sign of AD is the presence of numerous extracellular amyloid deposits (senile plaques) located next to degenerating axons and dendrites.
Most of all senile plaques are found in the cortex and limbic structures, in addition, amyloid deposits are observed in the walls of blood vessels of the brain - cortical and meningial arteries, arterioles, capillaries and (to a lesser extent) in veins.
Amyloid deposits are mainly localized on the abluminal membrane of these vessels.
The number of vessels damaged by amyloid clusters can vary greatly in different cases of AD with the same" density " of senile plaques.
It should be noted that similar amyloid deposits in a small amount and with a limited distribution in limbic structures are also found in the brains of elderly people who do not suffer from AD.
In addition to senile plaques, intraneuronal cytoplasmic filamentous structures - neurofibrillary plexuses were found in the brains of most patients who died from AD.
Most often, they are present in the bodies of those neurons whose degenerated axons are located in the area of senile plaques.
Numerous neurofibrillary plexuses are found in the neurons of the associative and limbic regions of the cortex, as well as in the neurons of the subcortical nuclei.
At the same time, such plexuses are very rare in other brain structures that are minimally affected in AD, for example, in the cerebellum [1].
Amyloid plaques and neurofibrillary tangles are characteristic, but not specific signs of AD.
Similar changes can be detected in healthy people during the aging process and in various other neurodegenerative diseases [7].
Thanks to the achievements of molecular biologists, geneticists, and neurochemists over the past decade, a number of fundamental data on the biochemical mechanisms associated with the development of AD have been obtained.
A detailed analysis of the components of amyloid deposits (senile plaques), so characteristic of this disease, was carried out (Table 2).
Table 2.
Chemical composition of senile plaques in Alzheimer's disease [1]
Connection groups
Substances found in senile plaques
Squirrels
B Amyloid protein (B A)
Proteoglycans: heparin sulfate, keratin sulfate, dermatan sulfate.
Apolipoproteins: ApoE, ApoJ
Enzymes
Acidic proteases(cathepsins B,D)
Glucose metabolism enzymes: glucosidase, hexoamidase
Aryl Sulfatase
Acid Phosphotase
Cholinesterase
Complement: C1q, C4, C5
Protease inhibitors
Cysteine protease inhibitor
Serine protease inhibitors: antichymotrypsin, antitrypsin, antithrombin
Substances contained in small quantities
Glycyration products
Metal ions: Al2+, Zn2+
The main component of senile plaques is b amyloid protein, which accounts for up to 25% of the dry weight of plaques.
The presence of proteoglycans and apolipoproteins in senile plaques is interesting because their ability to significantly accelerate the fibrillogenesis of synthetic amyloid has been established in vitro.
The detection of aluminum ions in senile plaques served as the basis for the assumption of the toxic effect of this element as the cause of AD.
However, more thorough studies carried out in recent years have shown that the penetration of aluminum into the brain and its binding to neurons is a secondary phenomenon caused by a violation of the protective functions of the blood - brain barrier.
The picture of pathological changes associated with a sharp increase in the intracellular concentration of calcium ions in AD is supplemented by disorders caused by the activation of calpain - protease by Ca2+ ions, the main substrate of which is neurofibrillar proteins (tubulin, spectrin, etc.).
A noticeable increase in the activity of calpain is a characteristic sign of AD; at the same time, the cytoskeleton of neurons is destroyed and the formation of neurofibrillar plexuses and strands [1].
Currently, several possible biochemical mechanisms of the development of this disease have been identified, among them: the ability of aggregated B A to enhance free radical processes in the brain, its ability to initiate apoptosis processes, an increase in excitotoxicity of excitatory amino acids in amyloids, a sharp violation of Ca2+ homeostasis in neurons mediated by the accumulation of B A, etc. (formulated by the author, citir. according to [1]).
Many experts believe that all the described biochemical mechanisms are involved in the pathogenesis of AD, as well as a number of other neurodegenerative diseases.
The relative role of each of them is determined by the individual characteristics of the body and the stage of the pathological process.
Deep degenerative damage to many brain structures in AD is accompanied by a violation of the functioning of almost all neurotransmitter systems.
In senile dementia, the lesion of the cholinergic system is much more pronounced (compared with other neurodegenerative diseases).
It was found that the release of AH from the vesicles into the synaptic cleft, as well as the process of choline reuptake, was significantly slowed down in the brains of patients with AD [1].
The sequence of molecular events leading to the development of Alzheimer's disease:
Missense mutations in the genes ARP, PS1,PS2
v
Altered proteolysis of ARP
v
Increased education in A 42 or general in A
v
Progressive accumulation of insoluble aggregates in A 42 in the intercellular space of the brain
v
Deposition of aggregated B 42 in the form of diffuse plaques
(in combination with proteoglycans and other amyloid activating substrates)
v
Aggregation in A 42 in diffuse plaques in A 42
Accumulation of certain proteins associated with plaques
v
"Inflammatory response":
* activation of microglia and release of cytokines
* astrocytosis and protein release
v
Progressive destruction of neurites
inside the amyloid plaques and in the neuropile
v
Violation of metabolic and ionic homeostasis
in neurons; oxidative damage
v
Modified kinase phosphotase
activity >hyperphosphorylation of ph >formation of PHF
v
Spreading neuronal neuritic dysfunction and
death of hippocampal and cortical cells with
progressive neurotransmitter deficiency
v
dementia
Some progress has been made in the search for substances that slow down the aggregation of secreted B A into a fibrillar cytotoxic form.
The search for such substances is very promising, because their interaction with B and ensembles in the extracellular space of the brain will help to avoid interference with the metabolism and functions of the soluble fragment of the APP [1].
2. Clinical manifestations
The disease is characterized by a progressive debilitating process, the central place in the development of which is occupied by memory disorders, which are the earliest and most typical manifestation of the disease.
A few years after the onset of the disease, disorders of praxis, speech, counting, writing, orientation and recognition naturally join, patients may have acute psychotic episodes, epileptic seizures, various extrapyramidal symptoms.
Eventually, deep total dementia develops with the disintegration of the personality, total aphasia, general physical exhaustion.
The average duration of the disease is about 10 years [2,3].
There is a weakening, primarily of short term memory, up to the loss of the ability to navigate in the simplest everyday situations; disorders of the emotional sphere, cognitive and motor functions.
BA, gradually progressing, turns still physically strong enough elderly people into helpless disabled people, unable to serve themselves and requiring constant care of others [1].
The current state of the problem:
A new human gene called humain (humain, HN) has been cloned and sequenced.
This gene encodes a protein that prevents the death of neurons during mutations in the genes that cause familial BA - the presenilins 1 and 2 genes, the ARP gene.
In addition, humaine affects the death of neurons caused by the expression of the amyloid peptide in A [9].
Proinflammatory cytokines can play a role in the pathogenesis of AD, and one of the genes of predisposition to the development of this disease is mapped on chromosome 6 in the region of localization of the gene of one of these cytokines, tumor necrosis factor - TNF... [8].
Relatives of patients with AD showed signs of dysfunction of deep brain structures.
The changes are more pronounced in relatives of patients with familial BA [10].
One of the risk factors is a low educational qualification (it increases by 1.8 times).
With a daily drinking of 3 glasses of wine, the risk of AD is 2 times less.
Risk factors include: high concentration of cholesterol and high density lipoproteins, increased platelet aggregation capacity, unbalanced diet.
The preventive effect of wine is explained by the presence of antioxidant polyphenols in it.
The probability of developing AD is affected by the degree of mental and physical activity [6].
It was found that the brain of elderly people and patients with AD contains a high concentration of herpes simplex virus type 1 (HSV 1).
It was noted that HSV 1 represents a high risk of AD development in individuals with a carrier of the apolipoprotein E gene allele.
PCR was used to check the content of other herpes family viruses in the brains of patients with AD: herpes virus type 6, HSV 2 and CMV.
Marked.
That the brain of patients with AD also contains large amounts of the herpes virus type 6 [11].
The diagnosis of the early stages of AD remains a complex clinical task, but the development of radioisotope methods for studying the brain, especially PECT, allows us to hope for a quick solution to this problem.
The conducted studies have shown a decrease in cerebral blood flow and glucose metabolism in the temporoparietal regions in patients with early stages of AD.
It has been shown that PECT detects AD with an accuracy of >90% 2.5 g earlier than clinical diagnostic methods, such as EEG, etc ., allow [4].
The prospects of an experimental search for ways to combat AD and related neurodegenerative disorders are discussed.
The role of genetic, cellular and biological genetic engineering research is emphasized.
The potential of antiamyloid vaccines, gamma secretase inhibitors, B A aggregation blockers, and copper removing chelates is also considered [5].
Conclusion
In clinical medicine, Alzheimer's disease is the first example of a common disease for which a leading genetic predisposition factor has been established.
In this regard, Alzheimer's disease can be considered as a kind of model for the development of methodological aspects of DNA testing in multifactorial human diseases.
Direct DNA diagnosis of Alzheimer's disease is a difficult task, which is associated with genetic heterogeneity, the relatively large size of the studied genes and the absence of major mutations in them.
The experience of such diagnostics in the world is available only in a relatively small number of well equipped laboratories specializing in the molecular genetic analysis of this disease [2].
Despite the well studied genetic and biochemical mechanisms of the disease development, effective measures to combat and prevent the occurrence of this pathology that could actually be applied in practice have not yet been found.
I think this is a question of the near future, judging by the intensity with which the search in this direction is going on.
List of literature
Eshchenko N. D. Biochemistry of mental and nervous diseases.
- St. Petersburg: Publishing House of St. Petersburg.
Un ta, 2004-200 p.
Illarioshkin S. N., Ivanova Smolenskaya I. A., Markova E. D. DNA diagnostics and medical genetic counseling in neurology.
- Moscow: Med. inf.
ag vo, 2002-591 p.
Hereditary diseases of the nervous system: hands for doctors /Edited by Yu.
E. Veltischev, P. A. Temin M.: Medicine, 1998-496 p.
Radioisotope image of the brain and diagnosis of Alzheimer's disease / Li Jian Nan, Shang Yu Kun / / Di er junyi daxue xuebao = Acad.
J. Second Mil.
Med.
Univ. - 2003-24, No. 4 p. 447-450 (RV, Biology, Human and Animal Physiology, Neurophysiology, 2003 No. 3).
Alzheimers disease and related dementias: The road to intervention // Exp.
Gerontol 2000-35, No. 4, pp.
433-437 (RS, Biology, Genetics and Cytology, Genetics of neurological diseases, 2003, No. 7).
Alzheimer: Letude Paquid / Letenneur L. / / Biofutur.
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Oct. - p. 16 (RS, Biology, Human and Animal Physiology, General and theoretical problems of normal and pathological physiology, 2002, No. 12).
A. rescue factor abolishing neuronal cell death bya wide spectrum of familial Alzheimers disease genes and Ab /Hashimoto Yuichi, Niikura Takako...
/ / Proc.
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Association of a.
haplotipe for tumor necrosis factor in siblings with late onset Alzheimer disease.
The NIMH Alzheimer disease genetics initiative/ Collins Julianne S.,Perry Rodney T. u.
a. // Amer.
J. Med.
Genet.
- 2000-96, No. 6 pp.
823-830 (RJ, Biology, Human and animal Physiology, General and theoretical problems of normal and pathological physiology, 2002, No. 12).
Atiologie und Pathogenese der Alzheimer Demenz / Kratsch T., Peters J., Fritzlich L. / / Wien.
med.
Wochenschr 2002-152, No. 3-4, pp.
72-76.
(Russian Language, Biology, Human and Animal Physiology, Neurophysiology, 2004 No. 4).
EEG alteration in the relations of patients with Alzheimers disease: Abstr.
8 th world Congress on PsychiatriCongress on Psychiatric Genetics, Versailles/ Ponomareva N., Fokin V.-2000-96, No. 4 p. 521 (RV, Biology, Genetics and Cytology, Genetics of Neurological Diseases, 2003, No. 12).
Herpesviruses in brainand Alzheimers disease / Lin Woan Ru, Wozhiak Matthew A.,Cooper Robert J., Wilcock Gordon K. // J. Pthol.
-2002-197, No. 3 p. 395-402 (Russian Language, Biology, Human and Animal Physiology, Neurophysiology, 2003 No. 3).
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