Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 7 • November 2012


Do Prions Play a Unifying Role in Neurodegenerative Diseases, Such as Alzheimer’s disease?

An article in a recent Science1 by Stanley B. Prusiner, the discoverer of prions, suggests that neurodegenerative diseases develop as a result of a native protein becoming refolded into a misfolded infectious state known as a prion.

As Prusiner explains in his article, “[t]he self-propagation of alternative conformations is a key feature of all prions.” He describes a study published in 2006 [cited in Prusiner’s article] in which researchers “inoculated human AD [Alzheimer’s disease] brain homogenates intracerebrally into marmosets. The marmosets developed Abeta [amyloid beta] plaques with incubating periods exceeding 3–5 years.” These results showed that the disease could be infectiously transmitted and, thus, Prusiner concludes, demonstrated the existence of a disease-causing prion in AD. “Similar results have been shown by Walker and Jucker and others [citation provided in paper] using transgenic AD mice.”1 Prusiner notes that the disease agent has been identified as being amyloid beta prions.

Prusiner points out that the amyloid beta proteins, consistent with (but not proving) the concept that they are prions, spread throughout the brain from the entorhinal cortex to many regions of the cortex. He concludes that “[m]eaningful treatments are likely to require cocktails of drugs that diminish the precursor protein, interfere with the conversion of precursors into prions, and/or enhance the clearance of prions.”

A paper2 published just a week before Prusiner’s article appeared in Science reported on how certain neurotoxic oligomers of amyloid beta 42, following a specific “off pathway” (that is, not following the nucleation-dependent fibril formation pathway) can result in “a replicating strain of oligomers that recruit amyloid beta 42 monomers and quantitatively converts them into LFAO [large fatty acid-derived oligomers] at the expense of fibrils, a mechanism similar to prion propagation.”2 As the authors summarize their study, “…the unique replicating property of off-pathway oligomers may hold profound significance for Alzheimer disease pathology.”

Finally, a very recent paper2B that included Stanley B. Prusiner as one of its authors, reported what they believe to be proof that in Alzheimer’s disease, the neurotoxic amyloid beta protein is self-propagating and, hence, is a prion. “Here we demonstrate that widespread cerebral deposition is induced following inoculation of Tg [transgenic] mice with purified brain-derived Abeta fibrils as well as aggregates composed of synthetic Abeta peptides. Although synthetic Abeta preparations exhibited lower specific bioactivity than Abeta aggregates derived from the brain, these results provide compelling evidence that Abeta aggregates are prions and that Abeta alone is sufficient for the formation of a self-propagating protein assembly.”2B “Although Abeta aggregates clearly behave like prions at the molecular level, there is currently no evidence that AD [Alzheimer’s disease] is infectious in the sense that it is communicable among humans. However, cerebral Abeta deposition in mice can be initiated by injection of Abeta aggregates into the periphery.” (See 2B for reference to paper that is cited in support of this statement.) “Recent transmission studies in cellular and mouse models of neurodegenerative diseases including the tauopathies, synucleinopathies, and amyotrophic lateral sclerosis (ALS) indicate that those diseases are also caused by self-propagating protein aggregates, i.e., prions.”2B

The usual way prion diseases from one animal “infect” another uninfected animal is via the uninfected animal eating prion-contaminated tissue, such as in reported cases of humans contracting mad cow disease. The authors of a 2010 paper3 also note that the infectious form of the prion protein is found in the urine of prion-infected animals and they report that the normal form of the prion protein is also found in normal human urine.

If it is true that AD can be caused by an infectious prion, then the approach to developing treatments will obviously have to be radically different. Current treatments are targeted at mechanisms (such as cholinergic dysfunction) that can explain only part of the AD pathology and that can be targeted to slow the development of the disease, but not reverse it. There has been some research on how to treat prion diseases, especially in the aftermath of the mad cow scare, and some of these treatments have been reported to prevent the conversion of the native species to the toxic prion or to enhance the clearance of prions. See, for example, references.4–10 (Note the promise of curcumin, resveratrol, and trehalose in the papers cited below.) [See “The Origami of Aging” in the September 2008 issue and See “Maintain your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue.]

References

1. Prusiner. A unifying role for prions in neurodegenerative diseases. Science 336:1511-3 (2012).
2. Kumar et al. Specific soluble oligomers of amyloid-beta peptide undergo replication and form non-fibrillar aggregates in interfacial environments. J Biol Chem 287(25):21253-64 (2012).
2B. Stohr et al. Purified and synthetic Alzheimer’s amyloid beta (Abeta) prions. Proc Natl Acad Sci USA 109(27):11025-30 (2012).
3. Dagdanova et al. Characterization of the prion protein in human urine. J Biol Chem 285(40):30489-30495 (2010).
4. Ahmad and Lapidus. Curcumin prevents aggregation in alpha-synuclein by increasing reconfiguration rate. J Biol Chem 287(12):9193-9 (2012).
5. Gu and Singh. Doxycycline and protein folding agents rescue the abnormal phenotype of familial CJD H187R in a cell model. Mol Brain Res 123:37-44 (2004).
6. Marambaud et al. Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J Biol Chem 280(45):37377-82 (2005).
7. Farquhar et al. Prophylactic potential of pentosan polysulphate in transissible spongiform encephalopathies. Lancet 353:117 (1999).
8. Bravo et al. Sulfated polysaccharides promote the assembly of amyloid beta1-42 peptide into stable fibrils of reduced cytotoxicity. J Biol Chem 283(47):32471-83 (2008).
9. Necula et al. Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282(14):10311-24 (2007).
10. Sarkar et al. Trehalose, a novel mTOR-independent autophagy enhancer accelerates the clearance of mutant Huntingtin and alpha-synuclein. J Biol Chem 2828:5641-52 (2007).

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