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The Journal of Neuroscience, July 2, 2003, 23(13):5645-5649

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Presenilin Redistribution Associated with Aberrant Cholesterol Transport Enhances -Amyloid Production In Vivo

Mark Burns,^1,2 Kate Gaynor,¹ Vicki Olm,¹ Marc Mercken,³ John LaFrancois,¹ Lili Wang,¹ Paul M. Mathews,^1,2 Wendy Noble,¹ Yasuji Matsuoka,^1,2 and Karen Duff^1,2

¹Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York 10962, ²Department of Psychiatry, New York University School of Medicine, New York, New York 10016, and ³Johnson and Johnson Pharmaceutical Research and Development, Janssen Pharmaceutica, B-2340 Beerse, Belgium

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 -C-terminal fragments (CTFs) of APP, but the level of -secretase and its activity were not affected. -Secretase activity and secreted APP generation were also not affected, suggesting CTFs increased because of decreased clearance. The level of presenilin-1 (PS-1) was unchanged, but -secretase activity was greatly enhanced, which correlated with an increase in A40 and A42 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 A levels.

Key words: amyloid; cholesterol; Niemann-Pick; NPC; -CTF; -secretase; presenilin; Rab 5; endosome

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Received Dec. 3, 2002; revised Apr. 24, 2003; accepted Apr. 24, 2003.

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