Pathogenesis of amyloid formation in Alzheimer's disease, Down's syndrome and scrapie.
Paired helical filaments (PHF) are abnormal fibrous structures found in human nerve cells and their processes. Ultrastructural studies of the proto-filaments that make up the PHF revealed that the individual proto-filaments have a different substructure from normal neurofilaments or any other known fibrous profiles. Studies using immunological and biochemical methods suggested that abnormally phosphorylated tau, ubiquitin and neurofilament peptides are part of the PHF. Deposits of amyloid fibres in Alzheimer's disease and senile dementia of the Alzheimer type (AD/SDAT) are found in meningeal and brain vessels, choroid plexus and neuritic plaques. In 1984 Glenner and Wong reported the sequence of a beta-protein isolated from cerebrovascular amyloid. We used the amino acid sequence of the cerebrovascular amyloid protein to synthesize oligonucleotide probes specific for the gene encoding this amyloid protein. Screening of a human brain cDNA library allowed us to isolate a clone which encodes the amyloid peptide. In situ hybridization studies and Southern blot analysis of a DNA sample isolated from a human-mouse hybrid cell line indicated that the corresponding genomic sequences of this cDNA clone are located on human chromosome 21. Using immunochemical and histochemical methods, we have identified the cells associated with the formation of the amyloid fibres. With immunochemical and biochemical methods we and others also showed that the protein constituting amyloid in AD/SDAT is different from amyloid in unconventional slow virus diseases.
Wisniewski
H M
HM
New York State Office of Mental Retardation and Developmental Disabilities, Institute for Basic Research in Developmental Disabilities, Staten Island 10314.
Wrzolek
M
M
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005815:Genetic Code; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism / Q000648:ultrastructure; D012608:Scrapie / Q000378:metabolism* / Q000473:pathology; D014777:Virus Diseases / Q000235:genetics
D000682:Amyloid