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Amyloid beta Protein and the Genetics of Alzheimer's Disease Dennis J. Selkoe
Known mutations leading to Alzheimer's disease:
While the genetic mutations that have been identified so far only amount to a very small percentage of the Alzheimer's cases seen each year, the more we learn about this disease the better prepared we are to fight it. New medicines are being evaluated that target gamma-secretase and the formation of amyloid plaques giving us hope that at some point in the future we may be able to prevent the onset of Alzheimer's from ever occurring.
When Alois Alzheimer first studied the disease in 1906, one of the abnormalities that he detected in his patient's brain was the presence of extracellular plaques made up of pieces of protein or amyloid. The protein that these fragments originated from was later identified and named the Amyloid beta Precursor Protein or APP for short. Soon after, scientists identified families suffering from hereditary Alzheimer's who possessed mutations in the gene for APP. However, these only accounted for a small percentage of Alzheimer's disease cases.
Alzheimer's disease is a harrowing form of dementia that slowly robs its victims of their memories, their personalities, and finally, their lives. The prevalence of this this disease, which most commonly afflicts the elderly, has increased in recent years in conjunction with our extended longevity. Few people in today's world can say that they or one of their loved ones have not had their lives touched by Alzheimer's.
J. Biol. Chem.,Aug 1996; 271: 18295.
The ways in which APP is processed by a cell are complex and involve the protein being cleaved by several enzymes called secretases. Also [link widoczny dla zalogowanych], not all pathways lead to the creation of amyloid beta. If an enzyme known as alpha-secretase cleaves APP first, then the product released does not accumulate into plaques. However, when it is cleaved first by an enzyme named beta-secretase, a second enzyme complex called gamma-secretase cuts it again to release amyloid beta.
Alzheimer's Disease: Genes, Proteins [link widoczny dla zalogowanych], and Therapy Dennis J. Selkoe
Read on
Research on Alzheimer's Causes and Prevention
APP, Genetics and Alzheimer's
Basic Alzheimer's Disease Biology
References:
History:
The creation of amyloid beta:
Physiol Rev, Apr 2001; 81: 741 - 766.
The amyloid hypothesis is the theory that Alzheimer's results from a malfunction along the biological pathway that leads to the creation of amyloid beta and it has lead to the development of promising new treatments that seek to prevent the dementia from occurring.
The amyloid that collects into plaques is a segment of APP that varies from 39 to 43 amino acids in length. The 42 amino acid length fragment, AB42, has been shown to be more likely to clump together into plaques. Mutations to the presenilins, enzymes which are part of the gamma-secretase complex, are another known factor in Alzheimer's disease, They increase the percentage of AB42 that is produced whenever amyloid beta is made and this also appears to lead to the onset of the disease.
It's important to understand that amyloid beta has a natural function in the human body and both processes occur in a healthy individual. Alzheimer's appears to result from errors leading to the production of too much or the wrong type of amyloid beta. APP mutations exist which lead to too much of the protein being cut by beta-secretase and not enough by alpha-secretase [link widoczny dla zalogowanych], with the end result being an overabundance of the amyloid beta and that seems to lead to Alzheimer's.
APP at a glanceMichael S. Wo
Conclusions:
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