Deciphering Alzheimer's disease: the amyloid precursor protein yields new clues

Article Abstract:

A molecule called amyloid beta protein precursor (APP), a fragment of which is amyloid beta protein (ABP), appears to play a role in Alzheimer's disease (AD). Patients with this progressive disorder, which leads to total loss of cognitive function, accumulate deposits of amyloid (a protein with some of the characteristics of starch) in their brains. ABP is a major component of this amyloid. A review is presented of the findings of seven research articles that recently appeared in Science magazine which described aspects of APP's structure and function. At the same time understanding was growing regarding the structure of normal APP, its greater distribution in AD brain than in normal brain was noted. ABP is found in younger people with Down syndrome, who also develop signs of brain aging at an early chronological age (40 years). In these cases, unlike in AD, pathologic brain cells are not present, implying that ABP may be present before such changes begin. Insights have been gained into how APP molecules are broken down to yield ABP. APP secretase, the protein that cleaves (breaks apart) the larger molecule, remains inactive prior to the time amyloid is deposited. It is not known which proportion of APP is cleaved to release ABP. The normal functions of APP are also under investigation, and these papers are cited. Finally, three reports are discussed concerning changes in APP in disease, including investigations of a very rare disease, hereditary cerebral hemorrhage with amyloidosis. This disorder involving APP has been found to affect four families in the Netherlands, and the genetic aspects are discussed. However, important questions about AD remain; it appears that study of beta-amyloidosis will hasten the development of treatment for this disabling disorder. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Cleavage of amyloid B peptide during constitutive processing of its precursor

Article Abstract:

Alzheimer's disease, a progressive condition leading to complete loss of cognitive function, is characterized by a number of degenerative changes in the brain. These include the appearance of senile plaques, collections of material surrounding a central core that contains a protein known as amyloid beta peptide (ABP). ABP is a smaller fragment of a molecule called amyloid precursor protein (APP), and the process whereby ABP is separated (cleaved) from its precursor is of considerable interest to researchers. Three forms of APP that contain ABP are known, but how ABP is generated in normal cellular processing remains to be determined; experiments were performed to answer this question. The results showed that cleavage of APP normally occurs within the ABP sequence as a result of the action of APP secretase (an enzyme). Thus, ABP is not normally formed and cannot be deposited in cells. The implication of this finding for AD is that in Alzheimer's disease ABP is deposited as the result of inefficient cleavage of APP by its enzyme. This defect leaves material within the cell that cannot be cleared by ordinary means, leading ultimately to formation of amyloid plaques. (Consumer Summary produced by Reliance Medical Information, Inc.)

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Alzheimer's disease: genotypes, phenotype, and treatments

Article Abstract:

Recent and previous studies together suggest that the four known genetic mutations associated with familial Alzheimer's disease increase the production or deposition of the amyloid beta protein in the brain. The gene defects and their phenotypes and possible treatments are discussed.

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