New Alzheimer's Treatment May Come From Discovering How Plaques Lead To Tangles
Now a new study published in the latest issue of Human Molecular Genetics appears to have uncovered an important clue about the link between plaques and tangles in Alzheimer's disease.
David R. Borchelt, a professor of neuroscience, and Guilian Xu, an assistant research scientist of the College of Medicine at the University of Florida in the US, and colleagues, used a mouse model to explore how amyloid plaques may trigger tau tangles.
Although both plaques and tangles are characteristic of Alzheimer's, amyloid plaques on their own do not produce the disease. Patients' symptoms become significantly worse when the tangles appear.
"Understanding how this sequence of events works is thought to be critical and could lead to new therapeutic approaches," Borchelt says in a press statement released this week.
We already know that a lot of the energy produced by cells goes into making sure the proteins they synthesize have the correct three-dimensional shape and are folded precisely in the manner that allows them to carry out vital cell functions. Any misshapen or misfolded proteins are ferried away, destroyed and recycled.
The researchers had a hunch that once amyloid plaques start to form between cells, this somehow interferes with the vital protein synthesis that occurs inside cells.
"... we sought to determine whether there is evidence of altered cytosolic protein folding by assessing whether amyloid deposition causes normally soluble proteins to misfold," they write in their study paper.
What they found in their "transgenic mice that model Alzheimer-type amyloidosis" was that as amyloid plaques accumulated outside cells, the proteins inside cells began to lose their ability to remain dissolved in the fluid environment within cells (cytosolic):
"Using a method that involved detergent extraction and sedimentation coupled with proteomic approaches, we identified numerous cytosolic proteins that show specific losses in solubility as amyloid accumulates," they report.
Borchelt, who is also director of the SantaFe HealthCare Alzheimer's Disease Research Center at UF and the McKnight Brain Institute, says:
"This deficiency in cell function could set the stage for allowing the formation of the neurofibrillary tangles that seem to be the key pathology to symptoms."
The suggestion is that as tau protein becomes affected by this loss of solubility, it loses its normal shape and begins to bind to other tau proteins.
Once this process gets under way, it gets out of control, upsetting the balance between protein synthesis and protein recycling, and the cell fills up with abnormally shaped tau clumps that produce the neurofibrillary tangles that are characteristic of Alzheimer's disease.
Some drug companies are already looking for new drugs that restore or improve protein folding in brain cells.
While this new study would suggest they are on the right track, the researchers warn that more studies need to be done before we can say we fully understand whether and how amyloid plaques lead to tau tangles. However, their findings do offer a new area to look at.
In the meantime, researchers in Germany have published a study that suggests Alzheimer's disease could be a result of protein spheres in the nucleus of cells giving out the wrong signal for cell division.
Written by Catharine Paddock PhD
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"Cytosolic proteins lose solubility as amyloid deposits in a transgenic mouse model of Alzheimer-type amyloidosis"; Guilian Xu, Stanley M. Stevens, Jr, Brenda D. Moore, Scott McClung, and David R. Borchelt; Human Molecular Genetics first published online 19 March 2013; DOI: 10.1093/hmg/ddt121; Link to Abstract.
Additional source: University of Florida News.
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