Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing

Article Abstract:

Alzheimer's disease is a pressing health problem; as more and more people live longer due to medical advances, a greater number will live long enough to develop dementia of the Alzheimer's type. Although estimates of the prevalence of Alzheimer's disease vary, it certainly affects more than 10 percent of the population over 65, and the percentage will rise as the population ages. The two major pathological features of Alzheimer's disease are tangled neurofibrils in some neurons and the presence of amyloid deposits around some nerves and blood vessels. The severity of the neurofibrillary tangles correlates with the severity of the dementia. However, neurofibrillary tangles are not specific for Alzheimer's disease, and occur in a number of neurological conditions. The same is not true for amyloid deposits, however. The amyloid containing senile plaques are highly specific to Alzheimer's disease, and occur in only a few other rare neurological disorders. For this reason, investigators believe that insights into the development of amyloid deposits may provide insights into the disease process itself. Amyloid, which gets its name from its starchy, amorphous appearance, is derived from a molecule called amyloid precursor protein (APP), which is a cell membrane glycoprotein. In the brains of Alzheimer's patients, this protein is cleaved to form an approximately four kilodalton fragment called beta-amyloid (beta/A4). In normal cells, this membrane protein has a short half-life. It appears transiently on the cell surface, and is then cleaved to release a fragment. The techniques of molecular biology have been used to examine the relationship of normal cleavage to the cleavage which produces the beta-amyloid fragment. The results indicate that the cleavage of APP in normal cells occurs within the region of the protein which would be the beta-amyloid fragment. Since the beta-amyloid region is divided by this process, intact beta-amyloid cannot be a product of the normal processing of APP. Therefore, the appearance of the beta-amyloid fragment of APP in patients with Alzheimer's disease seems to be the result of a pathological processing of this cell membrane protein. (Consumer Summary produced by Reliance Medical Information, Inc.)

Innovations, Glycoproteins, Protein metabolism, Protein research, Protein metabolism disorders

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Protease nexin-II (amyloid beta-protein precursor): a platelet alpha-granule protein

Article Abstract:

Although the cause or causes of Alzheimer's disease (a central nervous system disorder resulting in loss of cognitive abilities), Down's syndrome (a genetic disorder associated with mental retardation and other abnormalities), and some changes in the brain that accompany normal aging, remain unknown, one substance, amyloid beta-protein, has been found in the brains of patients with these conditions. This protein is derived from a larger protein, amyloid beta-protein precursor (APP), and insight into how these substances reach the brain could tell much about the genesis of central nervous system disease. A secreted form of APP is protease nexin-II (PN-II), and it is possible that this is a source of amyloid beta-protein, which may 'leak' into the brain through faulty blood vessel walls. However, neither PN-II/APP nor amyloid beta-protein has been found in blood. To find possible circulating reservoirs of these substances, components of blood were analyzed. It appeared that PN-II/APP was present in platelets (blood cells that are essential for clotting). Furthermore, more than half the PN-II/APP was located in the platelet alpha-granules (which also contain fibrinogen, a clotting factor). It is thus likely that PN-II/APP is secreted by platelets when they are activated. The protein appears to act as a growth factor in certain circumstances, such as at the site of a wound. Alterations in the walls of blood vessels could lead to platelet activation, with the release of PN-II/APP. Platelets from Alzheimer's disease patients appear abnormal, and may release PN-II/APP. Thus, a source of both PN-II/APP and its fragments has been identified that could allow these substances to accumulate, potentially damaging brain tissue. (Consumer Summary produced by Reliance Medical Information, Inc.)

Measurement, Proteins, Central nervous system diseases, Blood platelets

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A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease

Article Abstract:

To learn more about the genetic basis for familial (hereditary) Alzheimer's disease (a progressive neurological disease leading to complete cognitive loss), the DNA was analyzed from three generations of a family with this disorder. A mutation in the amyloid precursor protein (APP) has been identified in some patients with familial Alzheimer's disease. This protein is a precursor for amyloid, the substance typically deposited in senile plaques in the brain and in the walls of certain blood vessels of patients with this disorder. This study used the polymerase chain reaction, a method of amplifying small quantities of DNA, to examine exon 15 of the APP gene from tissue specimens or blood cells of affected family members. A substitution of a single base (point mutation) was found, phenylalanine for valine, in the part of the APP molecule that spans the cell membrane. The results constitute evidence that the mutation causes amyloid deposition and dementia in this family, although whether this is a direct result of the growth of amyloid in the brain, or an indirect consequence of altered APP function, cannot be determined. Substitutions of single amino acids have also been found in other forms of hereditary diseases involving abnormal deposition of amyloid (amyloidosis). (Consumer Summary produced by Reliance Medical Information, Inc.)

Genetic aspects

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