Journal
LIFE SCIENCES
Volume 91, Issue 23-24, Pages 1159-1168Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.lfs.2012.04.039
Keywords
ApoB; Amyloid beta; BACE-1; Tau; Synaptophysin
Funding
- National Center for Research Resources, a component of the NIH [P20RR17699]
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Aims: Elevated levels of circulating cholesterol are extrinsic factors contributing to the pathogenesis of sporadic Alzheimer's disease (AD). We showed previously that rabbits fed a cholesterol-enriched diet exhibited blood-brain barrier (BBB) dysfunction, increased accumulation of apolipoprotein B (ApoB) in brain neurons, and endolysosomes in brain had disturbed structures and functions. These effects were linked to increased amyloid beta (A beta) production, increased tau-pathology, and disrupted synaptic integrity. Because pathological changes to endolysosomes represent a very early event in sporadic AD, we determined here the extent to which ApoB-containing LDL cholesterol altered the structure and function of endolysosomes and contributed to the development of AD-like pathology in primary cultured neurons. Main methods: Cholesterol distribution and endolysosome morphology were determined histologically. Endolysosome pH was measured ratio-metrically with LysoSensor dye. Endolysosome enzyme activity was measured for acid phosphatase, cathepsins B and D, and beta-site APP cleaving enzyme 1 (BACE-1). AD-like pathologies, including increased production of A beta, increased tau-pathology, and disrupted synaptic integrity were determined using ELISA, immunoblotting, and immunostaining techniques. Key findings: Treatment of neurons with ApoB-containing LDL cholesterol increased endolysosome accumulation of cholesterol, enlarged endolysosomes, and elevated endolysosome pH. In addition, ApoB-containing LDL cholesterol increased endolysosome accumulation of BACE-1, enhanced BACE-1 activity, increased A beta levels, increased levels of phosphorylated tau, and decreased levels of synaptophysin. Significance: Our findings suggest strongly that alterations in the structure and function of endolysosomes play a key role in the exhibition of pathological features of AD that result from neuronal exposure to ApoB-containing LDL cholesterol. (C) 2012 Elsevier Inc. All rights reserved.
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