Presenilin redistribution associated with aberrant cholesterol transport enhances beta-amyloid production in vivo

• Published in: The Journal of neuroscience 2003-07, Vol.23 (13), p.5645-5649
• Main Authors: Burns, Mark, Gaynor, Kate, Olm, Vicki, Mercken, Marc, LaFrancois, John, Wang, Lili, Mathews, Paul M, Noble, Wendy, Matsuoka, Yasuji, Duff, Karen
• Format: Article
• Language: English
• Subjects: Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases; Animals; Apolipoproteins E - metabolism; Aspartic Acid Endopeptidases; Biological Transport - physiology; Brain Chemistry; Cellular/Molecular; Cholesterol - metabolism; Disease Models, Animal; Endopeptidases - metabolism; Endosomes - chemistry; Endosomes - metabolism; Gliosis - pathology; Homozygote; Intracellular Signaling Peptides and Proteins; Membrane Proteins - analysis; Membrane Proteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Niemann-Pick C1 Protein; Niemann-Pick Diseases - metabolism; Niemann-Pick Diseases - pathology; Presenilin-1; Proteins - metabolism
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/jneurosci.23-13-05645.2003

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.