title: Age-related modulation of γ-secretase activity in non-human primate brains.
abstract: Age-dependent accumulation of the amyloid-β peptide (Aβ) in the brain is a pre-condition for development of Alzheimer's disease. A relative increase in the generation of longer Aβ species such as Aβ42 and Aβ43 is critical for Aβ deposition, but the underlying mechanism remains unresolved. Here, we performed a cell-free assay using microsome fractions of temporal cortex tissues from 42 cynomolgus monkeys and found that Aβ40-generating γ-secretase activity (γ40) decreased with age, whereas Aβ42-generating γ-secretase activity (γ42) was unaltered. In ELISAs, more than 80% of monkeys over 20-years old showed evidence of Aβ accumulation in the temporal cortex. The ratio of γ42 to γ40 increased with age and correlated with the level of accumulated Aβ. These results suggest that γ-secretase activity undergoes age-related, non-genetic modulation and that this modulation may cause Aβ accumulation in aging brains. Similar modulation may predispose aged human brains to Alzheimer's disease.
authors: Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan. mnishimu@belle.shiga-med.ac.jp
authors: Masaki
authors: M
authors: Nishimura
authors: Shin-ichiro
authors: S
authors: Nakamura
authors: Nobuyuki
authors: N
authors: Kimura
authors: Lei
authors: L
authors: Liu
authors: Toshiharu
authors: T
authors: Suzuki
authors: Ikuo
authors: I
authors: Tooyama
mesh_terms: D000367:Age Factors; D000375:Aging; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D010450:Endopeptidases; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism; D053766:Presenilin-2 / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism* / Q000648:ultrastructure; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C469349:PSENEN protein, human; D053764:Presenilin-1; D053766:Presenilin-2; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases