Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 189, Issue 8, Pages 1621-1636Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.ajpath.2019.04.010
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Funding
- NIH [AG27465, AG051946, AG18879, CA16042, AI 28697]
- Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine
- AD Research Center Neuropathology Cores of University of Southern California National Institute on Aging (NIA) [P50 AG05142]
- University of California, Los Angeles NIA [P50 AG 16970]
- UC Irvine NIA [P50 AG16573]
- JCCC
- University of California, Los Angeles AIDS Institute
- David Geffen School of Medicine
- Chancellor's Office at University of California, Los Angeles
- NIA [R01 AG21055]
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Apolipoprotein E (apoE) colocalizes with amyloid-beta (A beta) in Alzheimer disease (AD) plaques and in synapses, and evidence suggests that direct interactions between apoE and A beta are important for apoE's effects in AD. The present work examines the hypothesis that apoE receptors mediate uptake of apoE/A beta complex into synaptic terminals. Western blot analysis shows multiple SDS-stable assemblies in synaptosomes from human AD cortex; apoE/A beta complex was markedly increased in AD compared with aged control samples. Complex formation between apoE and A beta was confirmed by coimmunoprecipitation experiments. The apoE receptors low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 (LRP1) were quantified in synaptosomes using flow cytometry, revealing up-regulation of LRP1 in early-and late-stage AD. Dual-labeling flow cytometry analysis of LRP1- and LDLR positives indicate most (approximately 65%) of LDLR and LRP1 is associated with postsynaptic density-95 (PSD-95)-positive synaptosomes, indicating that remaining LRP1 and LDLR receptors are exclusively presynaptic. Flow cytometry analysis of Nile red labeling revealed a reduction in cholesterol esters in AD synaptosomes. Dual-labeling experiments showed apoE and A beta concentration into LDLR and LRP1-positive synaptosomes, along with free and esterified cholesterol. Synaptic A beta was increased by apoE4 in control and AD samples. These results are consistent with uptake of apoE/A beta complex and associated lipids into synaptic terminals, with subsequent A beta clearance in control synapses and accumulation in AD synapses.
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