Neuronal origin of cerebral amyloidogenic proteins: their role in Alzheimer's disease and unconventional virus diseases of the nervous system.
The protein component of Alzheimer's disease amyloid (neurofibrillary tangles, amyloid plaque cores and congophilic angiopathy) is an aggregated polypeptide with a subunit mass of approximately 4 kDa (the A4 monomer). The aggregational properties of this monomer may explain the amyloidogenic nature of the protein: the native monomer forms dimers, tetramers and higher oligomeric species which are dependent on pH, ionic strength and concentration; the synthetic peptide corresponding to residues 1-28 spontaneously forms fibrils in vitro. Based on the degree of N-terminal heterogeneity, the A4 monomer aggregates first in neurons and later in the extracellular space. Using antisera raised against synthetic peptides, we can demonstrate that the N-terminus contains an epitope for neurofibrillary tangles, and the inner region of the molecule contains an epitope for the extracellular amyloid fibrils. There is a non-protein component of the amyloid (inorganic residues of aluminium silicate) which may be important in the deposition of the amyloid fibrils. There are several intriguing similarities between the amyloid fibrils and proteins of Alzheimer's disease when compared to the scrapie-associated filaments and proteins of the unconventional virus diseases (scrapie, kuru, Creutzfeldt-Jakob disease). Although there is no sequence homology between the proteins, we suspect they are formed as a result of similar biochemical processes. If the scrapie proteins and filaments are an integral part of the infectious agent, it follows that Alzheimer's disease is also an infectious process similar to scrapie. As they are host-encoded proteins, it is still feasible that both types are pathological by-products of independent diseases.
D000544:Alzheimer Disease / Q000209:etiology*; D000682:Amyloid / Q000096:biosynthesis* / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000502:physiology; D009422:Nervous System Diseases / Q000209:etiology*; D009474:Neurons / Q000378:metabolism; D014777:Virus Diseases / Q000209:etiology*
D000682:Amyloid; D009419:Nerve Tissue Proteins