Distinguishable effects of Presenilin-1 and APP717 mutations on amyloid plaque deposition

• Published in: Neurobiology of aging 2001-05, Vol.22 (3), p.367-376
• Main Authors: ISHII, Kazuhiro, LIPPA, Carol, POLLEN, Dan A, ST. GEORGE-HYSLOP, Peter H, II, Kunio, OHTAKE, Toshiyuki, KALARIA, Rajesh N, ROSSOR, Martin N, LANTOS, Peter L, CAIRNS, Nigel J, FARRER, Lindsay A, MORI, Hiroshi, TOMIYAMA, Takami, MIYATAKE, Fumiko, OZAWA, Kazuharu, TAMAOKA, Akira, HASEGAWA, Takashi, FRASER, Paul E, SHOJI, Shinichi, NEE, Linda E
• Format: Article
• Language: English
• Subjects: Adult; Age of Onset; Aged; Alzheimer Disease - epidemiology; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Apolipoproteins E - genetics; Biological and medical sciences; Cell Count; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Genotype; Humans; Immunohistochemistry; Male; Medical sciences; Membrane Proteins - genetics; Middle Aged; Mutation - genetics; Mutation, Missense - genetics; Neurology; Peptide Fragments - metabolism; Plaque, Amyloid - genetics; Plaque, Amyloid - metabolism; Plaque, Amyloid - pathology; Presenilin-1
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/s0197-4580(01)00216-0

Both APP and PS-1 are causal genes for early-onset familial Alzheimer's disease (AD) and their mutation effects on cerebral Abeta deposition in the senile plaques were examined in human brains of 29 familial AD (23 PS-1, 6 APP) cases and 14 sporadic AD cases in terms of Abeta40 and Abeta42. Abeta isoform data were evaluated using repeated measures analysis of variance which adjusted for within-subject measurement variation and confounding effects of individual APP and PS-1 mutations, age at onset, duration of illness and APOE genotype. We observed that mutations in both APP and PS-1 were associated with a significant increase of Abeta42 in plaques as been documented previously. In comparison to sporadic AD cases, both APP717 and PS-1 mutation cases had an increased density (measured as the number of plaques/mm(2)) and area (%) of Abeta42 plaques. However, we found an unexpected differential effect of PS-1 but not APP717 mutation cases. At least some of PS-1 but not APP717 mutation cases had the significant increase of density and area of Abeta40-plaques as compared to sporadic AD independently of APOE genotype. Our results suggest that PS-1 mutations affect cerebral accumulation of Abeta burden in a different fashion from APP717 mutations in their familial AD brains.