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Article ; Online: Quantitative Proteomic Analysis Reveals apoE4-Dependent Phosphorylation of the Actin-Regulating Protein VASP.

Cakir, Zeynep / Lord, Samuel J / Zhou, Yuan / Jang, Gwendolyn M / Polacco, Benjamin J / Eckhardt, Manon / Jimenez-Morales, David / Newton, Billy W / Orr, Adam L / Johnson, Jeffrey R / da Cruz, Alexandre / Mullins, R Dyche / Krogan, Nevan J / Mahley, Robert W / Swaney, Danielle L

Molecular & cellular proteomics : MCP

2023 Volume 22, Issue 5, Page(s) 100541

Abstract: Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is ... ...

Abstract	Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here, we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in vasodilator-stimulated phosphoprotein (VASP) S235 phosphorylation in a protein kinase A (PKA)-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.
MeSH term(s)	Actins/metabolism ; Alzheimer Disease/metabolism ; Apolipoprotein E3/genetics ; Apolipoprotein E3/metabolism ; Apolipoprotein E4/genetics ; Apolipoprotein E4/metabolism ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Phosphorylation ; Proteomics ; Animals ; Mice
Chemical Substances	Actins ; Apolipoprotein E3 ; Apolipoprotein E4 ; Apolipoproteins E ; vasodilator-stimulated phosphoprotein
Language	English
Publishing date	2023-04-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2075924-1
ISSN	1535-9484 ; 1535-9476
ISSN (online)	1535-9484
ISSN	1535-9476
DOI	10.1016/j.mcpro.2023.100541
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Article ; Online: The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation.

Nature neuroscience

2023 Volume 26, Issue 12, Page(s) 2104–2121

Abstract: Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare ... ...

Abstract	Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD), leading to earlier age of clinical onset and exacerbating pathologies. There is a critical need to identify protective targets. Recently, a rare APOE variant, APOE3-R136S (Christchurch), was found to protect against early-onset AD in a PSEN1-E280A carrier. In this study, we sought to determine if the R136S mutation also protects against APOE4-driven effects in LOAD. We generated tauopathy mouse and human iPSC-derived neuron models carrying human APOE4 with the homozygous or heterozygous R136S mutation. We found that the homozygous R136S mutation rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. The heterozygous R136S mutation partially protected against APOE4-driven neurodegeneration and neuroinflammation but not Tau pathology. Single-nucleus RNA sequencing revealed that the APOE4-R136S mutation increased disease-protective and diminished disease-associated cell populations in a gene dose-dependent manner. Thus, the APOE-R136S mutation protects against APOE4-driven AD pathologies, providing a target for therapeutic development against AD.
MeSH term(s)	Animals ; Humans ; Mice ; Alzheimer Disease/genetics ; Apolipoprotein E3/genetics ; Apolipoprotein E4/genetics ; Mutation/genetics ; Neuroinflammatory Diseases ; Tauopathies/genetics
Chemical Substances	Apolipoprotein E3 ; Apolipoprotein E4 ; ApoE protein, human ; Apoe protein, mouse
Language	English
Publishing date	2023-11-13
Publishing country	United States
Document type	Journal Article
ZDB-ID	1420596-8
ISSN	1546-1726 ; 1097-6256
ISSN (online)	1546-1726
ISSN	1097-6256
DOI	10.1038/s41593-023-01480-8
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Zs.A 4891: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Neuronal Apolipoprotein E4 Expression Results in Proteome-Wide Alterations and Compromises Bioenergetic Capacity by Disrupting Mitochondrial Function.

Orr, Adam L / Kim, Chaeyoung / Jimenez-Morales, David / Newton, Billy W / Johnson, Jeffrey R / Krogan, Nevan J / Swaney, Danielle L / Mahley, Robert W

Journal of Alzheimer's disease : JAD

2019 Volume 68, Issue 3, Page(s) 991–1011

Abstract: Apolipoprotein (apo) E4, the major genetic risk factor for Alzheimer's disease (AD), alters mitochondrial function and metabolism early in AD pathogenesis. When injured or stressed, neurons increase apoE synthesis. Because of its structural difference ... ...

Abstract	Apolipoprotein (apo) E4, the major genetic risk factor for Alzheimer's disease (AD), alters mitochondrial function and metabolism early in AD pathogenesis. When injured or stressed, neurons increase apoE synthesis. Because of its structural difference from apoE3, apoE4 undergoes neuron-specific proteolysis, generating fragments that enter the cytosol, interact with mitochondria, and cause neurotoxicity. However, apoE4's effect on mitochondrial respiration and metabolism is not understood in detail. Here we used biochemical assays and proteomic profiling to more completely characterize the effects of apoE4 on mitochondrial function and cellular metabolism in Neuro-2a neuronal cells stably expressing apoE4 or apoE3. Under basal conditions, apoE4 impaired respiration and increased glycolysis, but when challenged or stressed, apoE4-expressing neurons had 50% less reserve capacity to generate ATP to meet energy requirements than apoE3-expressing neurons. ApoE4 expression also decreased the NAD+/NADH ratio and increased the levels of reactive oxygen species and mitochondrial calcium. Global proteomic profiling revealed widespread changes in mitochondrial processes in apoE4 cells, including reduced levels of numerous respiratory complex subunits and major disruptions to all detected subunits in complex V (ATP synthase). Also altered in apoE4 cells were levels of proteins related to mitochondrial endoplasmic reticulum-associated membranes, mitochondrial fusion/fission, mitochondrial protein translocation, proteases, and mitochondrial ribosomal proteins. ApoE4-induced bioenergetic deficits led to extensive metabolic rewiring, but despite numerous cellular adaptations, apoE4-expressing neurons remained vulnerable to metabolic stress. Our results provide insights into potential molecular targets of therapies to correct apoE4-associated mitochondrial dysfunction and altered cellular metabolism.
MeSH term(s)	Adenosine Triphosphate/metabolism ; Animals ; Apolipoprotein E4/metabolism ; Cell Line, Tumor ; Energy Metabolism ; Mice ; Mitochondria/metabolism ; NAD/metabolism ; Neurons/metabolism ; Proteome/metabolism ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; Transcriptome
Chemical Substances	Apolipoprotein E4 ; Proteome ; Reactive Oxygen Species ; NAD (0U46U6E8UK) ; Adenosine Triphosphate (8L70Q75FXE)
Language	English
Publishing date	2019-03-15
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-181184
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Article ; Online: A common transcriptional mechanism involving R-loop and RNA abasic site regulates an enhancer RNA of APOE.

Watts, Jason A / Grunseich, Christopher / Rodriguez, Yesenia / Liu, Yaojuan / Li, Dongjun / Burdick, Joshua T / Bruzel, Alan / Crouch, Robert J / Mahley, Robert W / Wilson, Samuel H / Cheung, Vivian G

Nucleic acids research

2022 Volume 50, Issue 21, Page(s) 12497–12514

Abstract: ... Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA ... of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified ... does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length ...

Abstract	RNA is modified by hundreds of chemical reactions and folds into innumerable shapes. However, the regulatory role of RNA sequence and structure and how dysregulation leads to diseases remain largely unknown. Here, we uncovered a mechanism where RNA abasic sites in R-loops regulate transcription by pausing RNA polymerase II. We found an enhancer RNA, AANCR, that regulates the transcription and expression of apolipoprotein E (APOE). In some human cells such as fibroblasts, AANCR is folded into an R-loop and modified by N-glycosidic cleavage; in this form, AANCR is a partially transcribed nonfunctional enhancer and APOE is not expressed. In contrast, in other cell types including hepatocytes and under stress, AANCR does not form a stable R-loop as its sequence is not modified, so it is transcribed into a full-length enhancer that promotes APOE expression. DNA sequence variants in AANCR are associated significantly with APOE expression and Alzheimer's Disease, thus AANCR is a modifier of Alzheimer's Disease. Besides AANCR, thousands of noncoding RNAs are regulated by abasic sites in R-loops. Together our data reveal the essentiality of the folding and modification of RNA in cellular regulation and demonstrate that dysregulation underlies common complex diseases such as Alzheimer's disease.
MeSH term(s)	Humans ; R-Loop Structures ; RNA/genetics ; Alzheimer Disease/genetics ; Transcription, Genetic ; Apolipoproteins E/genetics
Chemical Substances	RNA (63231-63-0) ; Apolipoproteins E
Language	English
Publishing date	2022-12-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkac1107
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Zs.A 1067: Show issues

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Article: The J. David Gladstone Institutes.

Mahley, R W

Molecular medicine (Cambridge, Mass.)

1997 Volume 3, Issue 9, Page(s) 569–571

MeSH term(s)	Academies and Institutes ; Acquired Immunodeficiency Syndrome ; Alzheimer Disease ; California ; Cardiovascular Diseases ; Fellowships and Scholarships ; Virology
Language	English
Publishing date	1997-09
Publishing country	England
Document type	Journal Article
ZDB-ID	1283676-x
ISSN	1076-1551
ISSN	1076-1551
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Zs.A 4456: Show issues

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Article: Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology.

Mahley, R W / Huang, Y

Acta neurologica Scandinavica. Supplementum

2006 Volume 185, Page(s) 8–14

Abstract: The unique structural and biophysical features of apolipoprotein (apo) E4 - domain interaction and molten globule formation - have been correlated with the detrimental effects of apoE4 in neuropathology. Two examples of how the structure of apoE4 ... ...

Abstract	The unique structural and biophysical features of apolipoprotein (apo) E4 - domain interaction and molten globule formation - have been correlated with the detrimental effects of apoE4 in neuropathology. Two examples of how the structure of apoE4 determines the pathological outcome in neurons include apoE4 potentiation of amyloid beta-induced lysosomal leakage and apoptosis and the proteolytic cleavage of apoE synthesized by neurons. Thus, a new therapeutic target is to identify small molecules to modulate the inherent neuropathological structure of apoE4, i.e. to prevent domain interaction and to convert apoE4 to an apoE3-like molecule. A second therapeutic target is to inhibit the apoE-cleaving enzyme. This would prevent the generation of the reactive carboxyl-terminal fragments of apoE that enter the cytosol, disrupt the cytoskeleton, and cause neurodegeneration. ApoE4 is more susceptible than apoE3 to proteolytic cleavage and is thus more likely to cause detrimental effects in the central nervous system. It is predictable that apoE4 acts through various pathways to cause cognitive decline and neurodegeneration.
MeSH term(s)	Alzheimer Disease/etiology ; Apolipoprotein E4 ; Apolipoproteins E/physiology ; Apoptosis/physiology ; Humans ; Lysosomes/physiology ; Neurodegenerative Diseases/etiology ; Neurons/physiology ; Protein Conformation
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E
Language	English
Publishing date	2006
Publishing country	Denmark
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1956-2
ISSN	0065-1427
ISSN	0065-1427
DOI	10.1111/j.1600-0404.2006.00679.x
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Article: Heparan sulfate proteoglycan/low density lipoprotein receptor-related protein pathway involved in type III hyperlipoproteinemia and Alzheimer's disease.

Mahley, R W

Israel journal of medical sciences

1996 Volume 32, Issue 6, Page(s) 414–429

Abstract: The heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor-related protein (LRP) pathway plays a critical role in apolipoprotein (apo) E-containing lipoprotein metabolism in hepatocytes and other cells, including neurons. In this ... ...

Abstract	The heparan sulfate proteoglycan (HSPG)/low density lipoprotein (LDL) receptor-related protein (LRP) pathway plays a critical role in apolipoprotein (apo) E-containing lipoprotein metabolism in hepatocytes and other cells, including neurons. In this review, it will be shown that the HSPG sequestration step (i.e., the recruitment and trapping of remnant lipoproteins in the space of Disse in the liver) is an important component of remnant metabolism mediated by apo-E. In vitro studies indicate that the apo-E-containing lipoproteins must first interact with HSPG; only then does the LRP mediate lipoprotein uptake. The differential interaction of apo-EIII and the various mutant forms of apo-E with this pathway before internalization appears to be one factor that modulates the expression of recessive versus dominant type III hyperlipoproteinemia. Furthermore, it is now apparent that the HSPG/LRP pathway is involved in the delivery of apo-E to neurons, where apo-E alters neurite growth and cytoskeletal activity in these cells. Specifically, apo-EIV, which has been associated with the pathogenesis of Alzheimer's disease, inhibits neurite extension and microtubule formation subsequent to the interaction of apo-EIV with the HSPG/LRP pathway.
MeSH term(s)	Alzheimer Disease/metabolism ; Apolipoproteins E/metabolism ; Apolipoproteins E/physiology ; Heparan Sulfate Proteoglycans ; Heparitin Sulfate/metabolism ; Humans ; Hyperlipidemias/genetics ; Hyperlipoproteinemia Type III/metabolism ; Liver/metabolism ; Proteoglycans/metabolism ; Receptors, LDL/metabolism
Chemical Substances	Apolipoproteins E ; Heparan Sulfate Proteoglycans ; Proteoglycans ; Receptors, LDL ; Heparitin Sulfate (9050-30-0)
Language	English
Publishing date	1996-06
Publishing country	Israel
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	219691-8
ISSN	0021-2180
ISSN	0021-2180
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Zs.A 238: Show issues

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Article: Apolipoprotein E: far more than a lipid transport protein.

Mahley, R W / Rall, S C

Annual review of genomics and human genetics

2000 Volume 1, Page(s) 507–537

Abstract: First recognized as a major determinant in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E has emerged as an important molecule in several biological processes not directly related to its lipid transport function, including ... ...

Abstract	First recognized as a major determinant in lipoprotein metabolism and cardiovascular disease, apolipoprotein (apo) E has emerged as an important molecule in several biological processes not directly related to its lipid transport function, including Alzheimer's disease and cognitive function, immunoregulation, and possibly even infectious diseases. ApoE is a polymorphic protein arising from three alleles at a single gene locus. The three major isoforms, apoE4, apoE3, and apoE2, differ from one another only by single amino acid substitutions, yet these changes have profound functional consequences at both the cellular and molecular levels. ApoE3 seems to be the normal isoform in all known functions, while apoE4 and apoE2 can each be dysfunctional. Isoform (allele)-specific effects include the association of apoE2 with the genetic disorder type III hyperlipoproteinemia and with both increased and decreased risk for atherosclerosis and the association of apoE4 with increased risk for both atherosclerosis and Alzheimer's disease, impaired cognitive function, and reduced neurite outgrowth; isoform-specific differences in cellular signaling events may also exist. Functional differences in the apoE isoforms that affect (or did affect) survival before the reproductive years probably account, at least in part, for the allele frequencies of the present day.
MeSH term(s)	Alleles ; Animals ; Apolipoproteins E/chemistry ; Apolipoproteins E/genetics ; Apolipoproteins E/metabolism ; Arteriosclerosis/etiology ; Arteriosclerosis/genetics ; Biological Transport, Active ; Communicable Diseases/etiology ; Communicable Diseases/genetics ; Female ; Heart Diseases/etiology ; Heart Diseases/genetics ; Humans ; Hyperlipoproteinemia Type III/genetics ; Hyperlipoproteinemia Type III/metabolism ; Immunity/genetics ; Lipid Metabolism ; Lipoproteins/metabolism ; Male ; Models, Molecular ; Neurobiology ; Phenotype ; Polymorphism, Genetic ; Protein Isoforms/chemistry ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; Reproduction/genetics ; Risk Factors
Chemical Substances	Apolipoproteins E ; Lipoproteins ; Protein Isoforms
Language	English
Publishing date	2000
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Review
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev.genom.1.1.507
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Se 2016: Show issues

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Article: Is epsilon4 the ancestral human apoE allele?

Mahley, R W / Rall, S C

Neurobiology of aging

1999 Volume 20, Issue 4, Page(s) 429–430

MeSH term(s)	Animals ; Apolipoprotein E4 ; Apolipoproteins E/genetics ; Evolution, Molecular ; Female ; Humans ; Male
Chemical Substances	Apolipoprotein E4 ; Apolipoproteins E
Language	English
Publishing date	1999-07
Publishing country	United States
Document type	Comment ; Journal Article ; Review
ZDB-ID	604505-4
ISSN	1558-1497 ; 0197-4580
ISSN (online)	1558-1497
ISSN	0197-4580
DOI	10.1016/s0197-4580(99)00081-0
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Zs.A 1685: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Apolipoprotein E: cholesterol transport protein with expanding role in cell biology.

Mahley, R W

Science (New York, N.Y.)

1988 Volume 240, Issue 4852, Page(s) 622–630

Abstract: Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant ... ...

Abstract	Apolipoprotein E is a plasma protein that serves as a ligand for low density lipoprotein receptors and, through its interaction with these receptors, participates in the transport of cholesterol and other lipids among various cells of the body. A mutant form of apolipoprotein E that is defective in binding to low density lipoprotein receptors is associated with familial type III hyperlipoproteinemia, a genetic disorder characterized by elevated plasma cholesterol levels and accelerated coronary artery disease. Apolipoprotein E is synthesized in various organs, including liver, brain, spleen, and kidney, and is present in high concentrations in interstitial fluid, where it appears to participate in cholesterol redistribution from cells with excess cholesterol to those requiring cholesterol. Apolipo-protein E also appears to be involved in the repair response to tissue injury; for example, markedly increased amounts of apolipoprotein E are found at sites of peripheral nerve injury and regeneration. Other functions of apolipoprotein E, unrelated to lipid transport, are becoming known, including immunoregulation and modulation of cell growth and differentiation.
MeSH term(s)	Amino Acid Sequence ; Apolipoproteins E/genetics ; Apolipoproteins E/physiology ; Biological Transport ; Cholesterol/metabolism ; Gene Expression Regulation ; Humans ; Hyperlipoproteinemia Type III/genetics ; Hyperlipoproteinemia Type III/metabolism ; Immunity ; Lipid Metabolism ; Molecular Sequence Data ; Polymorphism, Genetic ; Protein Conformation ; Receptors, LDL/metabolism
Chemical Substances	Apolipoproteins E ; Receptors, LDL ; Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	1988-04-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.3283935
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Zs.MG 77: Show issues

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