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Differential Production of Amyloid Proteins Marks Hereditary Alzheimer's Disease

By BiotechDaily International staff writers
Posted on 24 Jun 2013
Alzheimer's disease (AD) researchers employing SILK (stable isotope linked kinetics) technology have shown that individuals with a hereditary form of AD overproduce type 42 amyloid beta protein, which readily accumulates in the amyloid plaques that characterize the disease.

Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and a strong genetic element. In patients suffering from this form of Alzheimer's disease (autosomal dominant hereditary), mutations in the presenilin proteins (PSEN1 and PSEN2) or the amyloid precursor protein (APP) can be found. The majority of these cases carry mutant presenilin genes. An important factor in the disease process in AD is the accumulation of amyloid beta (Abeta) protein. To form Abeta, APP must be cut by two enzymes, beta secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.

Until the development of SILK, there was no method to directly measure the production or clearance of Abeta. The SILK technique, which was first described in 2006, requires 36 hours to perform, but is the only published method that allows measurement of amyloid plaque formation and clearance in the living brain.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) recently used SILK technology to evaluate 11 subjects with Alzheimer’s mutations and compare the findings to those obtained from 12 related family members who did not have Alzheimer’s mutations.

Results revealed that the AD patients synthesized about 20% more Abeta42 than did family members who lacked the Alzheimer’s mutation. The fractional turnover rate of soluble Abeta42 relative to another form of amyloid protein Abeta40 was 65% faster in mutation carriers and correlated with amyloid deposition, consistent with increased deposition of Abeta42 into plaques, leading to reduced recovery of Abeta42 in cerebrospinal fluid (CSF).

“These results indicate how much we should target amyloid beta 42 with Alzheimer’s drugs,” said senior author Dr. Randall Bateman, professor of neurology at Washington University School of Medicine. “We are hopeful that this and other research will lead to preventive therapies to delay or even possibly prevent Alzheimer’s disease.”

The study was published in the June 12, 2013, issue of the journal Science Translational Medicine.

Related Links:
Washington University School of Medicine




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