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Published online on March 27, 2006, 10.1073/pnas.0600549103
PNAS | April 11, 2006 | vol. 103 | no. 15 | 5644-5651
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Inaugural Article
BIOLOGICAL SCIENCES / NEUROSCIENCE
Apolipoprotein E4: A causative factor and therapeutic target in neuropathology, including Alzheimer’s disease

Robert W. Mahley*,{dagger},{ddagger},§,¶,||, Karl H. Weisgraber*,{dagger},§,¶, and Yadong Huang*,{dagger},§,**

*Gladstone Institute of Neurological Disease and {dagger}Gladstone Institute of Cardiovascular Disease, 1650 Owens Street, San Francisco, CA 94158; and Departments of {ddagger}Medicine, **Neurology, and §Pathology, and Cardiovascular Research Institute, University of California, San Francisco, CA 94143

Contributed by Robert W. Mahley, January 30, 2006

The premise of this review is that apolipoprotein (apo) E4 is much more than a contributing factor to neurodegeneration. ApoE has critical functions in redistributing lipids among CNS cells for normal lipid homeostasis, repairing injured neurons, maintaining synapto-dendritic connections, and scavenging toxins. In multiple pathways affecting neuropathology, including Alzheimer’s disease, apoE acts directly or in concert with age, head injury, oxidative stress, ischemia, inflammation, and excess amyloid beta peptide production to cause neurological disorders, accelerating progression, altering prognosis, or lowering age of onset. We envision that unique structural features of apoE4 are responsible for apoE4-associated neuropathology. Although the structures of apoE2, apoE3, and apoE4 are in dynamic equilibrium, apoE4, which is detrimental in a variety of neurological disorders, is more likely to assume a pathological conformation. Importantly, apoE4 displays domain interaction (an interaction between the N- and C-terminal domains of the protein that results in a compact structure) and molten globule formation (the formation of stable, reactive intermediates with potentially pathological activities). In response to CNS stress or injury, neurons can synthesize apoE. ApoE4 uniquely undergoes neuron-specific proteolysis, resulting in bioactive toxic fragments that enter the cytosol, alter the cytoskeleton, disrupt mitochondrial energy balance, and cause cell death. Our findings suggest potential therapeutic strategies, including the use of "structure correctors" to convert apoE4 to an "apoE3-like" molecule, protease inhibitors to prevent the generation of toxic apoE4 fragments, and "mitochondrial protectors" to prevent cellular energy disruption.

mitochondria | neurodegeneration | cytoskeleton | protein folding

See accompanying Profile on page 5641.

Freely available online through the PNAS open access option.

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on May 2, 2000.

Author contributions: R.W.M., K.H.W., and Y.H. designed research; R.W.M., K.H.W., and Y.H. performed research; Y.H. contributed new reagents/analytic tools; R.W.M., K.H.W., and Y.H. analyzed data; and R.W.M., K.H.W., and Y.H. wrote the paper.

Conflict of interest statement: No conflicts declared.

||To whom correspondence should be addressed. E-mail: rmahley{at}gladstone.ucsf.edu

© 2006 by The National Academy of Sciences of the USA


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