'Harmless' prion protein linked to Alzheimer's disease
Non-infectious form of prion protein could cause brain degeneration.
Non-infectious prion proteins found in the brain may contribute to Alzheimer's disease, researchers have found.
The surprising new results, reported this week in Nature1, show that normal prion proteins produced naturally in the brain interact with the amyloid-ß peptides that are hallmarks of Alzheimer's disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-ß peptide. It was previously thought that only infectious prion proteins, rather than their normal, non-infectious counterparts, played a role in brain degeneration.
The results have yet to be confirmed in humans, but suggest that targeting the non-infectious prion protein (PrPc) could provide an alternative route to treating Alzheimer's disease. "The need is huge," says Paul Aisen, an Alzheimer's researcher based at the neurosciences department of the University of California, San Diego. "And it's great news for the field when a new idea is brought forth with strong evidence that can lead to new therapeutic strategies."
Alzheimer's disease has long been linked to the build-up of amyloid-ß peptides, first into relatively short chains known as oligomers, and then eventually into the long, sticky fibrils that form plaques in the brain. The oligomeric form of the peptide is thought to be toxic, but exactly how it acts in the brain is unknown.
Stephen Strittmatter and his colleagues at Yale University in New Haven, Connecticut searched for brain cell proteins that interact with amyloid-ß oligomers. To their surprise, they found PrPc, the normal, non-infectious prion protein.
Normal prion proteins are produced naturally in the brain, but can cause disease when they come into contact with an infectious form of the protein (PrPSc) that folds into an unusual conformation. These infectious prions convert innocuous prion proteins into the infectious form, which forms clumps and leads to neurodegenerative diseases, such as variant Creutzfeldt-Jakob disease, the human form of mad cow disease.
Strittmatter's team found that in brain slices taken from mice that were engineered to lack the prion protein, amyloid-ß did not cause defects in a process called long-term potentiation, which is important for long-term memory formation. Similarly, using an antibody to block the prion protein also prevented damage caused by the errant amyloid-ß peptides.
Researchers have struggled to determine what prion proteins normally do in the brain. Mice that lack the protein appear largely normal, with possible minor deficits in the generation of new neurons and responses to stress. A recent study found evidence that the prion protein may also be necessary for mice to have a normal sense of smell2.
Nevertheless, the results in mice suggest that blocking the protein may have unwanted side-effects, says Lennart Mucke, a neurologist at the Gladstone Institute of Neurological Disease in San Francisco, California. Although some are already at work to develop drugs that target the prion protein, these programmes target the infectious form of the protein and may not be useful in warding off Alzheimer's disease.
But Strittmatter and his colleagues mapped the region of the prion protein that interacts with amyloid-ß, giving researchers a clear target in the search for inhibitors of this interaction. Mucke, meanwhile, points out that an enzyme called a-secretase can cleave the prion protein at a site that would prevent it from binding to amyloid-ß. This same enzyme can also cleave amyloid-ß itself, meaning that enhancing that enzyme's activity could yield two strikes against Alzheimer's disease.
Although more work needs to be done to confirm the results in animal and human studies, Aisen says Alzheimer's disease researchers will welcome a new target in the fight against the frustrating disease. Clinical trials are underway to test drugs that aim to reduce the levels of amyloid-ß in the brain, but researchers are pessimistic about ever driving amyloid-ß levels down to zero. Meanwhile, treatments already on the market target symptoms of the disease, and not it's underlying cause.
"The treatments we have for Alzheimer's disease today are symptomatic and entirely inadequate," says Aisen. "There's no question that we need treatments that target the mechanisms behind neurodegeneration in Alzheimer's disease."
- Lauren, J. et al. Nature 457, 1128-1132 (2009).
- Le Pichon, C. E. et al. Nature Neuroscience 12, 60-69 (2008).