Role of Brain HDL ("good cholesterol")-Like Particles in Amyloid Beta Metabolism

Philip Verghese, PhD
Washington University, School of Medicine (Saint Louis, MO)

Mentors

David Holtzman, MD
Washington University (St. Louis, MO)
Year Awarded:
2010
Grant Duration:
April 1, 2010 to March 31, 2012
Disease:
Alzheimer's Disease
Award Amount:
$100,000
Grant Reference ID:
A2010613
Award Type:
Postdoctoral Fellowship
Award Region:
US Midwestern
Philip Verghese, PhD

Apolipoprotein E Isoforms and Amyloid Beta Metabolism

Summary

Apolipoprotein E appears to influence Alzheimer's disease pathogenesis in large part due to its ability to modulate amyloidbeta metabolism and structure. This ultimately influences the probability of amyloid beta aggregation. Our goal is to understand how apoE isoforms and lipid modulating molecules like ATP-binding cassette transporter A1 (ABCA1) take part in amyloid beta metabolism in the brain.

Details

Alzheimer's disease affects millions of people around the globe and the impact of this disease on society as a whole is enormous. Thus, it is necessary that we understand the cause of Alzheimer's disease and develop successful treatments. There is substantial evidence that the build-up of a small protein called amyloid beta in the brain produces a flow of events that drive brain cell collapse and ultimately causes Alzheimer's disease. Our research lab and others identified two important proteins called apolipoprotein E and ATP-binding cassette transporter A1 that, together, somehow influence amyloid beta production and breakdown. This eventually affects the likelihood of amyloid beta buildup in the brain. But we do not currently know the details of how these proteins control this amyloid beta buildup. So we are asking two important questions in order to understand the role of apolipoprotein E and ATP-binding cassette transporter A1 in amyloid beta production and breakdown. Our aims for this project are 1) study the factors that facilitate the binding of apolipoprotein E and amyloid beta 2) study how ATP-binding cassette transporter A1 controls the amyloid beta production and breakdown through apolipoprotein E proteins. The understanding of the connection between apolipoprotein E, amyloid beta and ATP-binding cassette transporter A1 will reveal additional ways that may be of therapeutic benefit in Alzheimer's disease.

Research Updates

Evidence suggests that the type of human Apolipoprotein E (APOE) isoforms inherited by an individual (ApoE2, E3, or E4) may shift the potential onset of Alzheimer Disease (AD) through changes to the probability of amyloid deposition and the age of onset of pathological changes. It has been proposed that differential direct interactions of ApoE isoforms with Aβ influences the metabolism of Aβ and may be one of the major explanations of how APOE influences the risk of AD. Numerous studies suggest that ApoE directly binds to Aβ and regulates Aβ metabolism; however, the molecular nature and how the direct interaction of ApoE/Aβ binding influences Aβ metabolism has not been detailed under physiological conditions. In this study, using physiological concentrations of cell secreted soluble Aβ (sAβ) and lipidated forms of ApoE isoforms, Dr. Verghese’s team shows strong evidence that ApoE and sAβ interactions occur minimally in the presence and absence of cells as assessed by multiple biochemical and analytical techniques. Further, there is minimal ApoE interaction with sAβ in the cerebrospinal fluid (fluid that surrounds the brain and spinal cord) of APOE3 and APOE4 human subjects. Despite minimal extracellular interactions with Aβ in fluid, the team finds that apoE isoforms regulate the metabolism of sAβ by astrocytes (star-shaped cells present in certain places in the brain and nervous system) and in interstitial fluid (liquid found between cells of the body) of mice that received human apoE infusions during brain Aβ microdialysis. On the basis of their findings, the team proposes that the ability of ApoE to influence Aβ clearance or aggregation is probably not through direct binding to Aβ in extracellular environment, but through its actions with other types of proteins, including receptors, transporters and/or particular sections of a cell’s membrane (protective envelope). These results will provide a new frame work for explaining how ApoE isoforms influence the risk of developing AD.

Publications

Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016 Sep 6;113(36):10186-91. doi: 10.1073/pnas.1609896113. Epub 2016 Aug 24. PubMed Icon Google Scholar Icon

Kim J, Eltorai AE, Jiang H, Liao F, Verghese PB, Kim J, Stewart FR, Basak JM, Holtzman DM. Anti-apoE immunotherapy inhibits amyloid accumulation in a transgenic mouse model of A? amyloidosis. J Exp Med. 2012 Nov 5. PubMed Icon Google Scholar Icon 

Castellano JM, Deane R, Gottesdiener AJ, Verghese PB, Stewart FR, West T, Paoletti AC, Kasper TR, Demattos RB, Zlokovic BV, Holtzman DM. Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood A? clearance in a mouse model of ?-amyloidosis. Proc Natl Acad Sci U S A. 2012 Sep ein E-independen-7. Epub 2012 Aug 27. PubMed Icon Google Scholar Icon

Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JÅ, Holtzman DM, Heneka MT. Critical role of astroglial apolipoprotein E and liver X receptor-? expression for microglial A? phagocytosis. J Neurosci. 2011 May 11;31(19):7049-59. PubMed Icon Google Scholar Icon

Verghese PB, Castellano JM, Holtzman DM. Apolipoprotein E in Alzheimer's disease and other neurological disorders. Lancet Neurol. 2011 Mar;10(3):241-52. Review. PubMed Icon Google Scholar Icon Verghese PB, Sasaki Y, Yang D, Stewart F, Sabar F, Finn MB, Wroge CM, Mennerick S, Neil JJ, Milbrandt J, Holtzman DM. Nicotinamide mononucleotide adenylyl transferase 1 protects against acute neurodegeneration in developing CNS by inhibiting excitotoxic-necrotic cell death. Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):19054-9. Epub 2011 Nov 4. PubMed Icon Google Scholar Icon

Basak JM, Verghese PB, Yoon H, Kim J, Holtzman DM. Low-density lipoprotein receptor represents an apolipoprotein E-independent pathway of A? uptake and degradation by astrocytes. J Biol Chem. 2012 Apr 20;287(17):13959-71. Epub 2012 Mar 1. PubMed Icon Google Scholar Icon

Verghese PB, Castellano JM, Garai K Jiang H, Shah AR, Frieden C, Holtzman DM. ApoE influences Aβ clearance despite minimal extracellular ApoE/Aβ association under physiological conditions (Under Review in PNAS).

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