Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo.
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.
Burns
Mark
M
Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, USA.
Gaynor
Kate
K
Olm
Vicki
V
Mercken
Marc
M
LaFrancois
John
J
Wang
Lili
L
Mathews
Paul M
PM
Noble
Wendy
W
Matsuoka
Yasuji
Y
Duff
Karen
K
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
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