Robert Mahley

Summary

Affiliation: University of California
Country: USA

Publications

  1. doi request reprint Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology
    Robert W Mahley
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, California 94158, United States
    J Med Chem 55:8997-9008. 2012
  2. doi request reprint Apolipoprotein e sets the stage: response to injury triggers neuropathology
    Robert W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Neuron 76:871-85. 2012
  3. ncbi request reprint Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond
    R W Mahley
    Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94141 9100, USA
    Curr Opin Lipidol 10:207-17. 1999
  4. pmc Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease
    Robert W Mahley
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 103:5644-51. 2006
  5. pmc Putting cholesterol in its place: apoE and reverse cholesterol transport
    Robert W Mahley
    Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    J Clin Invest 116:1226-9. 2006
  6. ncbi request reprint Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology
    R W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Acta Neurol Scand Suppl 185:8-14. 2006
  7. pmc Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing
    Robert W Mahley
    Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    J Clin Invest 117:94-8. 2007
  8. ncbi request reprint Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease
    Robert W Mahley
    Gladstone Institute of Neurological Disease 1650 Owens Street, San Francisco, CA 94158, USA
    Curr Alzheimer Res 4:537-40. 2007
  9. pmc Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
    Robert W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    J Lipid Res 50:S183-8. 2009
  10. ncbi request reprint Modulation of high-density lipoproteins in a population in istanbul, Turkey, with low levels of high-density lipoproteins
    Robert W Mahley
    Gladstone Institute of Cardiovascular Disease, San Francisco, California
    Am J Cardiol 96:547-55. 2005

Research Grants

Collaborators

Detail Information

Publications39

  1. doi request reprint Small-molecule structure correctors target abnormal protein structure and function: structure corrector rescue of apolipoprotein E4-associated neuropathology
    Robert W Mahley
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, California 94158, United States
    J Med Chem 55:8997-9008. 2012
    ..Structure-corrector-based therapies could prove to be highly effective for the treatment of many protein-misfolding diseases...
  2. doi request reprint Apolipoprotein e sets the stage: response to injury triggers neuropathology
    Robert W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Neuron 76:871-85. 2012
    ..Here, we review data supporting the hypothesis that apoE4 (> apoE3 > apoE2) has direct neurotoxic effects and highlight studies showing that blocking domain interaction reverses these detrimental effects...
  3. ncbi request reprint Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond
    R W Mahley
    Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94141 9100, USA
    Curr Opin Lipidol 10:207-17. 1999
    ..The isoform-specific effects of apolipoprotein E are currently being unraveled through detailed structure and function studies of this protein...
  4. pmc Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease
    Robert W Mahley
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 103:5644-51. 2006
    ....
  5. pmc Putting cholesterol in its place: apoE and reverse cholesterol transport
    Robert W Mahley
    Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    J Clin Invest 116:1226-9. 2006
    ..In lower species, these large HDLs are not atherogenic. Thus, CETP might not be essential for reverse cholesterol transport in humans, raising hope of using a CETP inhibitor to elevate HDL levels...
  6. ncbi request reprint Apolipoprotein (apo) E4 and Alzheimer's disease: unique conformational and biophysical properties of apoE4 can modulate neuropathology
    R W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Acta Neurol Scand Suppl 185:8-14. 2006
    ..It is predictable that apoE4 acts through various pathways to cause cognitive decline and neurodegeneration...
  7. pmc Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing
    Robert W Mahley
    Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA
    J Clin Invest 117:94-8. 2007
    ....
  8. ncbi request reprint Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease
    Robert W Mahley
    Gladstone Institute of Neurological Disease 1650 Owens Street, San Francisco, CA 94158, USA
    Curr Alzheimer Res 4:537-40. 2007
    ..Structural features that distinguish apoE4 and apoE3 determine their functional differences and hold the key to understanding how apoE4 is involved in Alzheimer's disease...
  9. pmc Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
    Robert W Mahley
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    J Lipid Res 50:S183-8. 2009
    ..The next phase in our understanding of apoE will be characterized by clinical intervention to prevent or reverse the detrimental effects of apoE4 by modulating its structure or blocking the pathological processes it mediates...
  10. ncbi request reprint Modulation of high-density lipoproteins in a population in istanbul, Turkey, with low levels of high-density lipoproteins
    Robert W Mahley
    Gladstone Institute of Cardiovascular Disease, San Francisco, California
    Am J Cardiol 96:547-55. 2005
    ..Why education failed to affect the HDL cholesterol levels in Turkish men remains unclear...
  11. ncbi request reprint Apolipoprotein E: far more than a lipid transport protein
    R W Mahley
    Gladstone Institute of Cardiovascular Disease, University of California at San Francisco, San Francisco, California 94141 9100, USA
    Annu Rev Genomics Hum Genet 1:507-37. 2000
    ..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...
  12. ncbi request reprint Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer's disease
    Yadong Huang
    Gladstone Institute of Neurological Disease, Gladstone Institute of Cardiovascular Disease, and the Department of Pathology, University of California, San Francisco, CA 94141 9100, USA
    J Mol Neurosci 23:189-204. 2004
    ..Some of these mechanisms might be suitable targets for the development of new treatments for AD...
  13. ncbi request reprint Apolipoprotein E4 potentiates amyloid beta peptide-induced lysosomal leakage and apoptosis in neuronal cells
    Zhong Sheng Ji
    Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141 9100, USA
    J Biol Chem 277:21821-8. 2002
    ....
  14. ncbi request reprint Managing dyslipidemia in Turkey: suggested guidelines for a population characterized by low levels of high density lipoprotein cholesterol
    Thomas P Bersot
    Gladstone Institute, Koç American Hospital, Istanbul, Turkey, and Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California, USA
    Anadolu Kardiyol Derg 2:315-22. 2002
    ..The most effective drug treatment available presently in Turkey relies on lowering LDL-C levels to optimize the TC/HDL-C ratio...
  15. ncbi request reprint Astroglial regulation of apolipoprotein E expression in neuronal cells. Implications for Alzheimer's disease
    Faith M Harris
    Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141 9100, USA
    J Biol Chem 279:3862-8. 2004
    ..Thus, neuronal expression of apoE is regulated by a diffusible factor or factors released from astrocytes, and this regulation depends on the activity of the Erk kinase pathway in neurons...
  16. ncbi request reprint Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol
    Thomas P Bersot
    Gladstone Institute, American Hospital, Istanbul, Turkey
    Am Heart J 146:1052-9. 2003
    ..Twenty percent of male patients with CHD in the United States fall into this category. The total cholesterol/HDL-C (TC/HDL-C) ratio predicts CHD risk regardless of the absolute LDL-C and HDL-C...
  17. ncbi request reprint Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice
    Walter J Brecht
    Gladstone Institute of Neurological Disease, San Francisco, California 94141 9100, USA
    J Neurosci 24:2527-34. 2004
    ..Neuron-specific proteolytic cleavage of apoE4 is associated with increased phosphorylation of tau and may play a key role in the development of AD-related neuronal deficits...
  18. pmc Apolipoprotein (apo) E4 enhances amyloid beta peptide production in cultured neuronal cells: apoE structure as a potential therapeutic target
    Shiming Ye
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 102:18700-5. 2005
    ..These findings provide insights into why apoE4 is associated with increased risk for Alzheimer's disease and may represent a potential target for drug development...
  19. ncbi request reprint Reactivity of apolipoprotein E4 and amyloid beta peptide: lysosomal stability and neurodegeneration
    Zhong Sheng Ji
    Gladstone Institute of Neurological Disease, Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, California 94158, USA
    J Biol Chem 281:2683-92. 2006
    ..Thus, apoE4 and Abeta1-42 may work in concert in neurons to increase lysosome formation while increasing the susceptibility of lysosomal membranes to disruption, release of lysosomal enzymes into the cytosol, and neuronal degeneration...
  20. ncbi request reprint Apolipoprotein A-V: a potential modulator of plasma triglyceride levels in Turks
    Ugur Hodoglugil
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, San Francisco, CA, USA
    J Lipid Res 47:144-53. 2006
    ..At least one of these alleles was present in approximately 40% of the Turks. Similar associations were observed for -1131T>C and S19W in white Americans living in San Francisco, California...
  21. ncbi request reprint Smoking and obesity make a bad problem worse: genetics and lifestyle affect high density lipoprotein levels in Turks
    Ugur Hodoglugil
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158, USA
    Anadolu Kardiyol Derg 6:60-7. 2006
    ..In conclusion, low HDL-C levels in Turks were modulated by genetic factors and their interaction with modifiable environmental factors, such as smoking and obesity...
  22. pmc Lipid- and receptor-binding regions of apolipoprotein E4 fragments act in concert to cause mitochondrial dysfunction and neurotoxicity
    Shengjun Chang
    Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 102:18694-9. 2005
    ..Thus, the lipid- and receptor-binding regions in apoE4 fragments act together to cause mitochondrial dysfunction and neurotoxicity, which may be important in Alzheimer's disease pathogenesis...
  23. ncbi request reprint Apolipoprotein E4 domain interaction occurs in living neuronal cells as determined by fluorescence resonance energy transfer
    Qin Xu
    Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94141, USA
    J Biol Chem 279:25511-6. 2004
    ..Thus, apoE4 domain interaction occurs in living neuronal cells and may be a molecular basis for apoE4-related neurodegeneration...
  24. ncbi request reprint Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc
    Faith M Harris
    Gladstone Institute of Neurological Disease, University of California, San Francisco, California 94141 9100, USA
    J Biol Chem 279:44795-801. 2004
    ..Thus, increased tau phosphorylation in apoE4 transgenic mice was associated with Erk activation and could be modified by zinc, suggesting that apoE4 and zinc act in concert to contribute to the pathogenesis of AD...
  25. pmc Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE epsilon4/epsilon4 genotype accelerates HIV disease progression
    Trevor D Burt
    Division of Experimental Medicine, Department of Medicine, and Division of Neonatology, Department of Pediatrics, University of California, San Francisco, CA 94110, USA
    Proc Natl Acad Sci U S A 105:8718-23. 2008
    ....
  26. ncbi request reprint Common polymorphisms of ATP binding cassette transporter A1, including a functional promoter polymorphism, associated with plasma high density lipoprotein cholesterol levels in Turks
    Ugur Hodoglugil
    Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158, USA
    Atherosclerosis 183:199-212. 2005
    ..In conclusion, we describe a functional promoter polymorphism (C-14T) and a coding sequence variant (V771M) of ABCA1 and their interactions with two other variants (R219K and I883M) on plasma HDL-C levels in Turks...
  27. pmc Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer's disease-like neurodegeneration and behavioral deficits in transgenic mice
    Faith M Harris
    Gladstone Institute of Neurological Disease, San Francisco, CA 94141 9100, USA
    Proc Natl Acad Sci U S A 100:10966-71. 2003
    ..Inhibiting their formation might inhibit apoE4-associated neuronal deficits...
  28. pmc Human prions and plasma lipoproteins
    Jiri G Safar
    Institute for Neurodegenerative Diseases, Department of Neurology, University of California, San Francisco, CA 94143, USA
    Proc Natl Acad Sci U S A 103:11312-7. 2006
    ..Whether detection of PrP(Sc) in VLDL and LDL particles can be adapted into an antemortem diagnostic test for prions in the blood of humans, livestock, and free-ranging cervids remains to be determined...
  29. ncbi request reprint Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus
    Qin Xu
    Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA
    J Neurosci 26:4985-94. 2006
    ..EGFPapoE reporter mice will be useful for studying the regulation of apoE expression in the CNS and might provide insights into the diverse mechanisms of apoE4-related neurodegeneration...
  30. pmc GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice
    Gang Li
    Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA
    Cell Stem Cell 5:634-45. 2009
    ..These findings suggest that GABAergic signaling can be targeted to mitigate the deleterious effects of apoE4 on neurogenesis...
  31. pmc Polymorphisms in the hepatic lipase gene affect plasma HDL-cholesterol levels in a Turkish population
    Ugur Hodoglugil
    Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA, USA
    J Lipid Res 51:422-30. 2010
    ..Thus, five LIPC SNPs, two novel, are associated with plasma HDL-C levels and hepatic lipase activity in two cohorts of Turkish subjects...
  32. doi request reprint Gender differences in the relationship of ENPP1/PC-1 variants to obesity in a Turkish population
    Sinan Tanyolac
    Department of Medicine and Diabetes Center, University of California, San Francisco Mt Zion Medical Center, San Francisco, California, USA
    Obesity (Silver Spring) 16:2468-71. 2008
    ..We find evidence that variants of ENPP1/PC-1 are associated with obesity in the male Turkish population; thus, these variants may contribute to the development of the obesity in these individuals...
  33. pmc Rosiglitazone increases dendritic spine density and rescues spine loss caused by apolipoprotein E4 in primary cortical neurons
    Jens Brodbeck
    Gladstone Institute of Neurological Disease and Gladstone Institute of Cardiovascular Disease, The J David Gladstone Institutes, 1650 Owens Street, San Francisco, CA 94158, USA
    Proc Natl Acad Sci U S A 105:1343-6. 2008
    ..Rosiglitazone rescued this detrimental effect. Thus, rosiglitazone might improve cognition in AD patients by increasing dendritic spine density...
  34. ncbi request reprint Relation between atherogenic dyslipidemia and the Adult Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of Metabolic Syndrome Project)
    Diego F Wyszynski
    Department of Medicine Genetics Program, Boston University School of Medicine, Boston, MA, USA
    Am J Cardiol 95:194-8. 2005
    ..In subjects aged <35 years, atherogenic dyslipidemia frequently occurs in the absence of other metabolic syndrome risk factors...
  35. ncbi request reprint Sources of variability in genetic association studies: insights from the analysis of hepatic lipase (LIPC)
    Ralph V Shohet
    Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA
    Hum Mutat 19:536-42. 2002
    ..Three novel LIPC polymorphisms were identified in the study (-1596insC, -2740A>G, and -2880G>C)...
  36. ncbi request reprint Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia
    Yi Yu
    Department of Medicine Genetics Program, Boston University School of Medicine, Boston, MA, USA
    J Lipid Res 46:2202-13. 2005
    ..These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci...
  37. pmc LDL-cholesterol concentrations: a genome-wide association study
    Manjinder S Sandhu
    Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK
    Lancet 371:483-91. 2008
    ..We therefore did a genome-wide association study of LDL-cholesterol concentrations...
  38. ncbi request reprint High density lipoprotein cholesterol in coronary artery patients: is it as low as expected?
    Robert W Mahley
    Anadolu Kardiyol Derg 6:94-6; author reply 96. 2006
  39. pmc Profile of Robert W. Mahley
    Regina Nuzzo
    Proc Natl Acad Sci U S A 103:5641-3. 2006

Research Grants4

  1. Genetic Determinants: Low HDL, High Triglycerides, Obes*
    Robert Mahley; Fiscal Year: 2003
    ....
  2. EXTRAMULAR RESEARCH FACILITIES CONSTRUCTION
    Robert Mahley; Fiscal Year: 2003
    ..Finally, funds are requested to equip a Behavioral Core Laboratory, which is essential for characterizing mouse models of human disease. ..
  3. Targeting Apolipoprotein E4-related Neuropathology
    Robert Mahley; Fiscal Year: 2004
    ..Ultimately, it will be our goal to take "hits" to lead compounds that may give rise to a drug that prevents or retards apoE4-related neuropathology. ..