Alzheimer’s Disease and Prions
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Amyloid fibrils are insoluble, highly organized protein aggregates. Deposition of these microscopic fibrils is associated with a number of degenerative diseases such as Alzheimer’s and Parkinson’s diseases, type II diabetes and prion diseases, including Creutzfeldt Jakob disease (CJD) and mad cow disease. Individual fibrils polymerize into highly stable, insoluble cross-linked masses. These structures are toxic to cells, although the reason for this is unclear. In some cases, the protein deposits physically disrupt tissue structure. In other cases, small amyloid-like oligomers seem to cause cell death directly. There has also been speculation that amyloid fibrils might puncture cells and cause problems such as ionic imbalances, but the truth is, at the present time, we really don’t know why these protein deposits are such a problem. In transmissible spongiform encephalopathies (prion diseases such as mad cow disease, scrapie and vCJD), the prion protein acts as an infectious agent which jump-starts self-polymerization of the normal, soluble prion protein counterpart, resulting in amyloid deposits and cell death, leading to the formation of plaques and spongiform degeneration in brain tissue, which eventually leads to death.
It has previously been believed that degenerative diseases such as Alzheimer’s and Parkinson’s diseases differ from prion diseases in that they are non-infectious. This conclusion was made after a number of experiments failed to show that post-mortem brain tissue samples from disease victims failed to transmit the disease to experimental animals (unlike prion diseases, where brain and other tissues are clearly infectious).
The clear difference between non-infectious amyloid diseases and infectious prion diseases just became a lot murkier with the publication of a recent paper in the journal Science (Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Meyer-Luehmann M, et al. Science. 2006 313: 1781- 1784). By injecting amyloid-containing brain extracts from people with Alzheimer’s disease into the brains of a strain of transgenic mice are predisposed to develop an Alzheimer’s-like condition due to overproduction of the amyloid precursor protein, the researchers were able to induce similar pathological conditions in the animals. When they denatured or depleted the amyloid protein in the extracts with antibodies, the ability of the extract to cause disease was reduced or abolished. In addition, immunization of the host animal against the amyloid protein also prevented transmission of the condition. Most strikingly of all, the phenotype of the disease induced in experimental animals depended on both the host and the source of the agent, suggesting the existence of polymorphic amyloid strains with varying biological activities. This is highly reminiscent of prion strains, and has never been observed before.
There is currently no evidence that amyloid diseases are transmissible between humans in the same sense as prion diseases, but these similarities between the two clearly related types of disease could shed light on the origins of Alzheimer’s disease, which is poorly understood. In the United States alone, 4.5 million people suffer from Alzheimer’s disease, and 20 million from type II diabetes. There is a desperate need to improve our understanding of the pathology underlying these illnesses. With the publication of the recent paper in Science, we may just have moved one step closer.
When you put this work together with another recent paper showing that RNAi can suppress prion protein polymerization and significantly prolong the survival of scrapie-infected mice (Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice. Pfeifer A, et al. J Clin Invest. 2006 116: 3204-3210), hopes for Alzheimer’s disease sufferers seem to be improving, although there’s a long way to go yet before this technology becomes a practical treatment.
You summerized those articles well. Good post. BTW, it’s really astonishing, but even if Alzheimer is infectious, it could only be transferred by brain extract, so we shouldn’t start to fear.
this article should have included what are the prions and how they are generated in the body/
Fair point Rupa, try this: Prions
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