×îÐÂÂ鶹ÊÓƵ

Non-Infectious Prion Protein Linked to Alzheimer’s Disease

A region of amyloid plaque in the brain of a person with Alzheimer's disease. Medical Microscopy Sciences, Cardiff University School of Medicine. All rights reserved by Wellcome Images.

The prion protein, notorious for causing fatal neurodegenerative disorders such as Creutzfeldt-Jakob disease and mad cow disease, may also be an accomplice in Alzheimer's disease, according to a new study. In this case, it's not the infectious misfolded prion protein causing the problem but the cellular form, whose function is relatively unknown.

Alzheimer's disease is marked by clumps of protein fibers called amyloids that accumulate into "plaques" around nerve cells in the brain, leading to the progressive loss of function. The main protein fragment found in these plaques, amyloid-ß peptide, is created by the improper cleavage of a protein called amyloid precursor protein (APP). Over time, amyloid-ß peptides transform into small clusters known as oligomers, which then develop into the long, sticky fibers that form plaques around brain cells. Scientists are uncertain if amyloid-ß oligomers act directly or through cell surface receptors to affect thinking and decision-making, but most agree that they're toxic to brain.

A team of scientists led by Dr. Stephen Strittmatter at Yale University reasoned that if there were cell surface receptors on brain cells that bound amyloid-ß oligomers, they might play a role in altering nerve cell function. Their search for these proteins was supported by NIH's ×îÐÂÂ鶹ÊÓƵ Institute of Neurological Disorders and Stroke (NINDS), ×îÐÂÂ鶹ÊÓƵ Institute of Drug Abuse (NIDA) and the NIH Medical Scientist Training Program.

In the February 26, 2009, edition of Nature, the researchers reported their discovery that a protein called PrP binds amyloid-β oligomers. The normal, non-infectious form of this protein, PrP^c, is found on the cell surface of brain cells. When misfolded into its PrP^Sc form, the protein becomes the infectious prion already known to be involved in several fatal neurodegenerative disorders, including bovine spongiform encephalopathy ("mad cow" disease) in cattle, Creutzfeldt-Jakob disease in humans, scrapie in sheep, and chronic wasting disease in deer and elk.

The researchers found that amyloid-β oligomers specifically bind cells with PrP^c. The interaction doesn’t depend on the misfolded PrP^Sc version of the protein.

The researchers next explored whether this interaction might play a part in causing disease. Learning and long-term memory are known to be hindered in Alzheimer’s patients because of a deficiency in a process called long-term potentiation (LTP).  To examine the role of the amyloid-β-PrP^c interaction on LTP, the scientists exposed slices of mouse hippocampus, a brain region critical for learning and memory, to amyloid-β oligomers. The amyloid-β oligomers inhibited LTP in normal mice, but not in mice lacking the PrPc protein.  Blocking the interaction between amyloid-β oligomers and PrP^c also prevented the deleterious effect.

This study suggests that PrP^c acts at an early stage of Alzheimer’s disease development, binding amyloid-β oligomers to advance the process of neurodegeneration. PrP^c is thus a promising target for potential therapies. The researchers mapped the region on PrP^c that interacts with the amyloid-β oligomer. This part of the protein, in particular, would be a prime target for potential Alzheimer’s pharmaceuticals.

—by Nancy Van Prooyen