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Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS

Robert W Mahley1, Karl H Weisgraber, Yadong Huang

  • 1Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA. rmahley@gladstone.ucsf.edu

Journal of Lipid Research
|December 25, 2008
PubMed

Insights

Apolipoprotein E (apoE) variants, particularly apoE4, contribute to cardiovascular, neurological, and infectious diseases due to distinct structural features. Future research aims to develop interventions targeting apoE4

Area of Science:

  • Biochemistry and Molecular Biology
  • Genetics and Disease Pathogenesis
  • Immunology and Infectious Diseases

Background:

  • Apolipoprotein E (apoE) plays crucial roles beyond lipid metabolism.
  • Structural variations among apoE isoforms (apoE2, apoE3, apoE4) influence their function and disease association.
  • ApoE4 is a significant genetic risk factor for Alzheimer's disease and other pathologies.

Purpose of the Study:

  • To elucidate the structure-function relationships of apoE isoforms.
  • To understand the detrimental effects of apoE4 in various diseases.
  • To explore potential clinical interventions for apoE4-related conditions.

Main Methods:

  • Structure/function studies of apolipoprotein E isoforms.
  • Analysis of apoE's role in lipoprotein metabolism and receptor binding.
  • Investigation of apoE's influence on cardiovascular, neurological, and infectious disease susceptibility.

Main Results:

  • ApoE2 exhibits defective low-density lipoprotein (LDL) receptor binding due to altered receptor-binding region structure, explaining type III hyperlipoproteinemia.
  • ApoE4 is strongly linked to Alzheimer's disease and other neuropathologies, exacerbated by genetic, metabolic, and environmental factors.
  • ApoE4 influences susceptibility to parasitic, bacterial, and viral infections, notably accelerating HIV/AIDS progression and opportunistic infections in homozygotes.

Conclusions:

  • Distinct structural features of apoE isoforms, especially apoE4, underlie their varied roles in disease.
  • ApoE4's detrimental effects span cardiovascular, neurological, and infectious disease domains.
  • Future clinical strategies will focus on modulating apoE4 structure or its mediated pathological processes.

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