Different disease types associated with distinct amyloid-beta prion strains found in Alzheimer's patients

January 9, 2018 by Bob Yirka, Medical Xpress report
Diagram of the brain of a person with Alzheimer's Disease. Credit: Wikipedia/public domain.

An international team of researchers has found different disease type associations with distinct amyloid-beta prion strains in the brains of dead Alzheimer's patients. In their paper published in Proceedings of the National Academy of Sciences, the group describes their study of sliced brain fragments and what they learned about the nature of amyloid-beta prions.

Prior research has found a connection between protein clumps in the brain and Alzheimer's disease. Prior research has also shown that the protein clumps are a mutant type of amyloid beta, which results in the growth of plaques in the brain. In this new effort, the researchers have found evidence indicating that there are distinct types of amyloid-beta prion strains which can be associated with different types of brain diseases.

The study consisted of dissecting and studying the brains of 41 patients who had died of Alzheimer's disease. Slices of brain tissue were doused with a fluorescent dye known to bind to amyloid bindings. The researchers studied the samples with confocal spectral imaging. Doing so, the group reports, revealed different types of disease associations between unique amyloid-beta strains. The researchers also found evidence that suggested mutant amyloid-beta can take on the self-propagating structure of prions, in which they form more self-replicating prions.

One of the goals of research surrounding Alzheimer's disease and other dementia ailments is to find a way to diagnose the particular ailment so that it can be treated with drugs or other therapies specifically designed for it. Currently, the only way to accurately diagnose Alzheimer's disease is to study the after a patient has died. The researchers with this new effort suggest their findings are a step toward this goal. They further suggest that probes of the future might be sensitive enough to distinguish the different they have seen in their work, which would allow doctors to design treatments specifically suited to individual patients. There is no cure for Alzheimer's disease, but there are drugs that can slow its progression—thus, if the disease could be diagnosed earlier, before obvious mental impairments present, treatment could begin earlier, giving more productive years.

Explore further: 'Pac-Man' gene implicated in Alzheimer's disease

More information: Carlo Condello et al. Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease, Proceedings of the National Academy of Sciences (2018). DOI: 10.1073/pnas.1714966115

Abstract
Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of Aβ deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT Aβ, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant Aβ40 fibrils into transgenic mice expressing only WT Aβ induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant Aβ40 prions induce a conformation of WT Aβ similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial Aβ prion conformations, which kinetically dominate the spread of prions in the brain.

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egehrman
1 / 5 (1) Jan 09, 2018
"The PROBLEM with most Government and University informational websites is that no attempt is made to critique the research reports, making it impossible for others to understand the significance of these data. There is much controversy regarding the causality of TSEs(and Alzheimer's). Our research shows that prion amyloid (the TSE research focus for the past 30 years) is the result of a bacterial infection. This controversy directly reflects on Louis Pasteur's efforts to prove that replicating crystals are not the cause of infectious disease, but instead bacteria are the culprits. Too bad we have to rehash this controversy."
Dr. Frank Bastian (more at tseresearchcenter.org )
FredJose
2 / 5 (1) Jan 10, 2018
There is no cure for Alzheimer's disease, but there are drugs that can slow its progression—thus, if the disease could be diagnosed earlier, before obvious mental impairments present, treatment could begin earlier, giving patients more productive years.

This is exactly where the problem really lies.
There's a quick jump to use drugs instead of finding the real cause and dealing with it.

So far most indications are that too much sugar in the diet plus an overload of transformed omega-3 fats are responsible. Ingesting a constant load of trans-fats from roasting nuts or vegetable fats for instance, coupled to lack of exercise are most likely the main culprits.

So reversing or eliminating those issues should be the first port of call, NOT drugs.

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