title: Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo.
abstract: Epidemiology, in vitro, and in vivo studies strongly implicate a role for cholesterol in the pathogenesis of Alzheimer's disease (AD). We have examined the impact of aberrant intracellular cholesterol transport on the processing of the amyloid precursor protein (APP) in a mouse model of Niemann-Pick type C (NPC) disease. In the NPC mouse brain, cholesterol accumulates in late endosomes/lysosomes. This was associated with the accumulation of beta-C-terminal fragments (CTFs) of APP, but the level of beta-secretase and its activity were not affected. Alpha-secretase activity and secreted APPalpha generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but gamma-secretase activity was greatly enhanced, which correlated with an increase in Abeta40 and Abeta42 levels. These events were associated with abnormal distribution of PS-1 in the endosomal system. Our results show that aberrant cholesterol trafficking is associated with the potentiation of APP processing components in vivo, leading to an overall increase in Abeta levels.
authors.affiliation: Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Burns
authors.forename: Kate
authors.initials: K
authors.lastname: Gaynor
authors.forename: Vicki
authors.initials: V
authors.lastname: Olm
authors.forename: Marc
authors.initials: M
authors.lastname: Mercken
authors.forename: John
authors.initials: J
authors.lastname: LaFrancois
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Mathews
authors.forename: Wendy
authors.initials: W
authors.lastname: Noble
authors.forename: Yasuji
authors.initials: Y
authors.lastname: Matsuoka
authors.forename: Karen
authors.initials: K
authors.lastname: Duff
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D001692:Biological Transport / Q000502:physiology; D001923:Brain Chemistry; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000378:metabolism; D011992:Endosomes / Q000737:chemistry / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1; D011506:Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001057:Apolipoproteins E; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D053764:Presenilin-1; D011506:Proteins; D002784:Cholesterol; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse