An update was made on Alzheimer’s disease, which is the most common cause of dementia. Aspects related to chromosomes 21 and 17. Mutations in the amyloid precursor protein gene, located on chromosome 21, are responsible for 5 to 20% of cases of early familial Alzheimer’s disease.
The amyloid precursor protein, when processed by an amyloidogenic pathway, originates beta amyloid, which is deposited in senile plaques and causes direct toxic effects on neurons. On chromosome 17 is the gene that codes for the synthesis of the Tau protein. Mutations in this gene cause an irreversible phosphorylation of the protein that prevents its normal function and facilitates its self-aggregation, forming neurofibrillary tangles. Although still under study,
Alzheimer’s disease (AD) has become a growing medical, psychiatric, neurological, epidemiological, social and economic problem, particularly in countries with a high life expectancy. 1
There are an estimated 18 million people with dementia worldwide. In Cuba, between 70,000 and 100,000 people suffer from AD or another cause of dementia, a figure that will double by 2020. 2
Alzheimer’s dementia can be classified according to the age of onset in presenile or early onset, which appears before 65 years and senile or late onset, that is, onset after 65 years. Based on the presence or absence of a family history of the disease, it is classified into familial AD and sporadic AD, respectively. However, these classifications are not exclusive. 3
The development achieved by genetics has made it possible to demonstrate the involvement of several chromosomes in the development of the disease. Chromosomes 1, 14, and 21 are associated with early-onset familial forms. 4 While the late-onset forms appear linked to chromosomes 12 and 19.4 However, most cases of AD cannot be explained genetically; For these cases, hypotheses have been raised, including those that affect genetic aspects, those that suggest the existence of possible unidentified infectious agents, or due to the action of unknown toxins, whether environmental or endogenous. 5 The influence of all these factors would increase the risk of suffering from the disease throughout life.
In this work, the study of chromosome 21 and the amyloid beta protein was deepened, since there are many findings that relate the deposit of excessive amounts of this protein among the first causes of the disease. In addition, aspects related to chromosome 17 and the Tau protein were discussed, because the latter is the main constituent of neurofibrillary tangles, the number of which is directly related to the intensity of dementia. However, it is important to note that these are not the only aspects involved in the pathogenesis of the disease.
The first fact that involved chromosome 21 with AD was that individuals with Down syndrome (trisomy 21) invariably developed clinicopathological features of the disease, if they lived over 30 years. 6 Subsequent studies of senile plaques, the first observable pathological event in AD, showed that its main constituent was beta amyloid (ßA).
SsA, a peptide of variable length (39-43 amino acids) and a size of 4-6 kDa, is a natural product of the metabolism of amyloid precursor protein (ASP). 7ASF is encoded by a gene located on chromosome 21, in the 21q 11.2-q21.1 region, and has the structural characteristics of membrane proteins, a long amino-terminal extracellular segment and a short carboxyl-terminal intracellular segment. 8 The ASF gene contains 18 exons and probably originates a family of at least 8 different transmembrane isoforms, which are differentiated by the presence or absence of exons 7, 8, 9 and 15.
The isoforms, which are expressed in neurons (isoform of PPA with 695, 714, 751 and 770 aa) that contain exon 15 are more amyloidogenic and release much more ßA peptide (42) than non-neuronal isoforms. 9ASF is expressed in many cells and tissues in the body, including neurons, smooth muscle cells in the vascular wall, and platelets. 10 Despite the time that it has been studied, the function of PPA in the cell is still unknown.
It is thought to act as a receptor bound to membrane G proteins, through which it sends chemical signals into the cell. 11 It is also known that its expression is increased during cellular stress phenomena, although the mechanisms that induce this increase or its relationship with the development of the disease are unknown. 4