Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation.
The 39- to 43-amino acid amyloid beta-protein (A beta), which is progressively deposited in cerebral plaques and blood vessels in Alzheimer disease (AD), is secreted by cultured human cells during normal metabolism. In studies of cell lines transfected with beta-amyloid precursor protein (beta APP) cDNAs, the beta APP mutation K670N/M671L found in a Swedish familial AD (FAD) pedigree has previously been shown to cause a marked augmentation of A beta secretion. Here, we have conducted blinded analyses of beta APP metabolism in primary skin fibroblasts from affected members of the Swedish FAD pedigree and their unaffected siblings or spouses. These fibroblasts continuously secrete a homogenous population of A beta molecules starting at Asp-1 (D672 of beta APP). We found a consistent and significant approximately 3-fold elevation of A beta release from all biopsied skin fibroblasts bearing the FAD mutation. No significant alterations of other metabolic derivatives of beta APP were detected. The elevated A beta levels were found in cells from both patients with clinical AD and presymptomatic subjects. Thus, A beta overproduction in this FAD pedigree is not a secondary event but is consistent with a causal role in the development of the disease. Increased A beta secretion can begin many years prior to onset of symptoms, even in peripheral tissues, indicating that it does not require preexisting neural abnormalities.
Citron
M
M
Department of Neurology, Harvard Medical School, Boston, MA.
Vigo-Pelfrey
C
C
Teplow
D B
DB
Miller
C
C
Schenk
D
D
Johnston
J
J
Winblad
B
B
Venizelos
N
N
Lannfelt
L
L
Selkoe
D J
DJ
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000302:isolation & purification; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007668:Kidney; D008715:Methionine / Q000378:metabolism; D010649:Phenylalanine / Q000378:metabolism; D017354:Point Mutation; D012867:Skin / Q000378:metabolism; D013462:Sulfur Radioisotopes; D013548:Sweden; D014316:Tritium
D016229:Amyloid beta-Peptides; D013462:Sulfur Radioisotopes; D014316:Tritium; D010649:Phenylalanine; D008715:Methionine