Link to Alzheimer's
 Read with caution! This post was written during early stages of trying to understand a complex scientific problem, and we didn't get everything right. The original author no longer endorses the content of this post. It is being left online for historical reasons, but read at your own risk. |
update 2013-04-04: this post is deprecated, please see PrP / amyloid beta interactions and the prion / Alzheimer’s connection for a more complete treatment of this subject.
“Prion-like mechanisms in neurodegenerative diseases,” Frost and Diamond, Nat Rev Neurosci (2010)
https://hopecenter.wustl.edu/?p=4107
Many non-infectious neurodegenerative diseases are associated with the accumulation of fibrillar proteins. These diseases all exhibit features that are reminiscent of those of prionopathies, including phenotypic diversity and the propagation of pathology. Furthermore, emerging studies of amyloid-beta, alpha-synuclein and tau–proteins implicated in common neurodegenerative diseases–suggest that they share key biophysical and biochemical characteristics with prions. Propagation of protein misfolding in these diseases may therefore occur through mechanisms similar to those that underlie prion pathogenesis. If this hypothesis is verified in vivo, it will suggest new therapeutic strategies to block propagation of protein misfolding throughout the brain.
“Interaction between prion protein and toxic ameloid beta assemblies can be therapeutically targeted at multiple sites,” Freir et. al. inc. Collinge, Nature Communications (2011)
http://www.nature.com/ncomms/
A role for PrP in the toxic effect of oligomeric forms of Aβ, implicated in Alzheimer’s disease (AD), has been suggested but remains controversial. Here we show that PrP is required for the plasticity-impairing effects of ex vivo material from human AD brain and that standardized Aβ-derived diffusible ligand (ADDL) preparations disrupt hippocampal synaptic plasticity in a PrP-dependent manner. We screened a panel of anti-PrP antibodies for their ability to disrupt the ADDL–PrP interaction. Antibodies directed to the principal PrP/Aβ-binding site and to PrP helix-1, were able to block Aβ binding to PrP suggesting that the toxic Aβ species are of relatively high molecular mass and/or may bind multiple PrP molecules. Two representative and extensively characterized monoclonal antibodies directed to these regions, ICSM-35 and ICSM-18, were shown to block the Aβ-mediated disruption of synaptic plasticity validating these antibodies as candidate therapeutics for AD either individually or in combination.
“Proin link to Alzheimer’s,” Nature (2002)
http://www.nature.com/nature/
The hypothesis that soluble amyloid- peptide oligomer plays a central role in Alzheimer’s disease is well established, yet no mechanistic basis for A oligomer effects on neurons has been described. Several lines of evidence point to the existence of a high-affinity cell-surface receptor for soluble A oligomers on neurons as central to Alzheimer’s disease pathology and now cellular prion protein PrPC has been identified as a candidate for that role. PrP, a plasma membrane glycoprotein associated with lipid rafts, binds A oligomers selectively with high affinity and mediates the deleterious effects of the peptide. These data raise the possibility that PrPC-specific drugs might have therapeutic potential in Alzheimer’s, and point to an unexpected link between infectious prion diseases and Alzheimer’s disease.
“Prions involved in some Alzheimer’s,” Hopkin, Scientific American (2009)
http://www.scientificamerican.
Scientists at Yale University have discovered that amyloid beta, a protein involved in Alzheimer’s disease, can damage brain cells by binding to prion proteins, which are themselves infamous because, in their abnormal form, they cause things like mad cow disease.
Amyloid beta is best known as the protein that forms the giant plaques that riddle the brains of people with Alzheimer’s. Those plaques contain billions of copies of amyloid beta all stuck together in one gloppy mess. But the protein also exists in a more soluble form, either in single units or in small groups of 50 or 100. These smaller clusters don’t cause the same large-scale mayhem as plaques, but they do damage neurons, impairing their ability to learn. And the Yale researchers wanted to find out how.
They discovered that amyloid beta binds to the prion proteins normally found on neurons. What’s more, the prions ramp up amyloid beta’s neurotoxic effects. Take away the prions and amyloid-beta clusters are harmless, findings published in the journal Nature. So drugs that prevent this amyloid–prion coupling could be a potent weapon against Alzheimer’s.
“In vitro and in vivo neurotoxicity of prion protein oligomers,” Plos Pathogens, Simoneux et. al., based out of Scripps (2007)
http://www.plospathogens.org/
http://www.scripps.edu/news/
There is a growing belief that intermediates in the formation of the protease-resistant prion protein PrPsc (sometimes referred to as PrP* [25]), rather than PrPsc itself, are the pathogenic forms of PrP [10,11,13,14]. Moreover, there is evidence from other brain amyloidoses that soluble oligomeric forms of the disease-associated protein constitute the neurodegenerative trigger [21–24].
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The present study establishes ß-PrP oligomers as a major neurotoxic species in vitro and in vivo, which likely represents the culprit PrP* responsible for the development of transmissible spongiform encephalopathy–linked neurodegeneration. Targeting ß-PrP oligomers, and their hydrophobic domain in particular, will allow researchers to devise rational neuroprotective treatments for these highly debilitating diseases.
From the press release:
The study’s results also showed that exposure of a specific surface region of the prion protein oligomer was required to initiate this common neurotoxic mechanism; antibodies that recognized this region were able to inhibit cellular toxicity and prevent neuronal death.
“In our in vitro studies, there was a dramatic antibody effect—if you block this region of the oligomers, you completely inhibit neuronal toxicity,” she said. “This region represents a very good therapeutic target, but there may be other target regions as well.”
The scientists’ in vivo findings with mouse models supported the picture that small prion aggregates, rather than plaque-type prion deposits, were responsible for neuronal dysfunction and death.
“Our new work demonstrates that the prion-induced neurodegeneration mechanism we uncovered in prion diseases is similar to that of other diseases such as Alzheimer’s, Huntington’s, and Parkinson’s,” Lasmezas said. “The degree of this commonality is remarkable, and our findings open new avenues for the development of neuroprotective strategies that directly target toxic prion oligomers.”
“Anchorless Prion Protein Results in Infectious Amyloid Disease without Clinical Scrapie” by Bruce Chesebro et. al, based out of Scripps
June 3, 2005 issue of Science. See http://www.sciencemag.org.
http://www.scripps.edu/
In the latest issue of the journal Science, the researchers describe the effect of removing a stretch of amino acids at the COOH end of the protein—called the glycophosphoinositol (GPI) anchor. This GPI anchor is essential for anchoring the prion protein into the membranes of cells, where it is believed this host prion protein interacts with the abnormal disease-producing isoform to yield more and more of the disease associated prion protein. Suspecting that this anchor may also be essential to the pathogenesis of prion diseases, the scientists removed it and looked at the effect of the removal on prion disease pathogenesis.
By taking off this anchor, the researchers showed that the prion protein still folded but was no longer able to attach in normal amounts onto the surface of cells. They then looked at the effect of the anchorless prions on the disease in vivo, and they found evidence that the GPI anchor plays a role in prion disease pathogenesis. Transgenic mice that express a form of prion protein without the GPI anchor no longer show the normal characteristics of clinical prion disease when they are infected with infectious prions. That is, they do not develop a progressive neurodegenerative disease fatal by 160 to 170 days after infection. Unexpectedly, these mice lived past 600 days with minimal symptoms.
They found that the anchorless prions instead induced a disease that mimicked Alzheimer’s—deposits of amyloid fibrils associated with dystrophic neurons were observed. However unlike Alzheimer’s, in which a different protein called “Ab” is deposited, there were heavy deposits of the disease-associated prion protein.
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However, the GPI-anchorless prion proteins didn’t cause amyloid disease in a classical sense—they were merely converted from a non-amyloid to an amyloid form that became deposited in the brain. The mice showed minimal clinical manifestations.
“The Prion Diseases,” Stanley Prusiner, Scientific American (1995)
http://mvc.bioweb.dcccd.edu/
Striking Similarities
Ongoing research may also help determine whether prions consisting of other proteins play a part in more common neurodegenerative conditions, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. There are some marked similarities in all these disorders. As is true of the known prion diseases, the more widespread ills mostly occur sporadically but sometimes “run” in families. All are also usually diseases of middle to later life and are marked by similar pathology: neurons degenerate, protein deposits can accumulate as plaques, and glial cells (which support and nourish nerve cells) grow larger in reaction to damage to neurons. Strikingly, in none of these disorders do white blood cells-those ever present warriors of the immune system-infiltrate the brain. If a virus were involved in these illnesses, white cells would be expected to appear.
Recent findings in yeast encourage speculation that prions unrelated in amino acid sequence to the PrP protein could exist. Reed B. Wickner of the NIH reports that a protein called Ure2p might sometimes change its conformation, thereby affecting its activity in the cell. In one shape, the protein is active; in the other, it is silent.