Senile dementia of the Alzheimer's type is a growing social and economic problem for our demographically aging population. The brains of persons who have died of Alzheimer's Disease (AD) contain large abnormal deposits of fibrillar material. It has recently been shown that the brains from two infectious diseases that bear many strong resemblences to AD, Creutzfeldt Jakob Disease of humans and scrapie of sheep, also accumulate large numbers of abnormal fibrils which are similar, though not identical, to those of AD. Scrapie brain fractions enriched for fibrils retain significant amounts of infectivity and it is proposed that the infectious agent consits of the fibrils themselves or, alternatively hypothetical small subunits of the fibrils, termed """"""""prions"""""""". It is claimed that """"""""prions"""""""" are subviral in size and contain no nucleic acid. While the fibrils bear some resemblence to the filamentous viruses of protists and plants, they can be disrupted without destroying infectivity. Although the """"""""prion"""""""" is repeatedly claimed to have been purified by one laboratory, no definite structure has been provided. Moreover it has been shown that the major fibrillar protein and therefore the """"""""prion"""""""" protein is coded by a host gene expressed in multiple tissues in both infected and uninfected animals. As a consequence, if it is the fibrils themselves or their hypothetical """"""""prion"""""""" subunits that are infectious, they will constitute a new form of pathogen with far reaching implications for all other diseases, including AD, which accumulate similar material. Alternatively, the infectivity could reside in a small virus, adventitiously associated with the fibril preparations in insufficient concentration to be detected against the high background of fibrillar protein. It is proposed to establish whether or not the fibrils or some subunit of the fibrils are infectious by attempting to separate the fibrils or their subunits from infectivity using sonication to destroy fibrils or using antifibril antibodies to aggregate fibrils, followed by size, density, charge and affinity separations using centrifugation, electrophoresis and column chromatography. Procedures will be verified by using conventional viruses as internal markers, and the distribution of fibrillar protein will be monitored by ELISA assay, Western blot detection of electrophoresed protein, and electron microscopy. After destruction or removal of the fibrils, preparations will be tested for the destruction or removal of infectivity as well. If the two can be separated then clearly, the fibrils or their subunit can not be the agent. If infectivity remains tenaciously associated with fibrils or their subunits, then those methods that prove most effective in separating fibrils from other brain components can be used for further purification. If the fibrils are viruses they should contain a viral nucleic acid that is not found in the host. We propose to determine whether or not such a nucleic acid exists as part of the fibril. Such a nucleic acid could form the basis for a diagnostic reagent for scrapie and AD, if AD is caused by a similar agent.
| Rohwer, R G (1992) Alzheimer's disease transmission: possible artifact due to intercurrent illness. Neurology 42:287-8 |
