TY - JOUR T1 - Presenilin Redistribution Associated with Aberrant Cholesterol Transport Enhances β-Amyloid Production <em>In Vivo</em> JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5645 LP - 5649 DO - 10.1523/JNEUROSCI.23-13-05645.2003 VL - 23 IS - 13 AU - Mark Burns AU - Kate Gaynor AU - Vicki Olm AU - Marc Mercken AU - John LaFrancois AU - Lili Wang AU - Paul M. Mathews AU - Wendy Noble AU - Yasuji Matsuoka AU - Karen Duff Y1 - 2003/07/02 UR - http://www.jneurosci.org/content/23/13/5645.abstract N2 - 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 β-C-terminal fragments (CTFs) of APP, but the level of β-secretase and its activity were not affected. α-Secretase activity and secreted APPα generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but γ-secretase activity was greatly enhanced, which correlated with an increase in Aβ40 and Aβ42 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 Aβ levels. ER -