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Mechanism Explains Link Between Apolipoprotein E And Alzheimer's Disease

Date:
June 13, 2008
Source:
Cell Press
Summary:
Scientists have discovered a previously unknown mechanism by which apolipoprotein E, a molecule whose mutation is linked to Alzheimer's disease, stimulates degradation of sticky amyloid beta protein within the brain. The research may lead to a powerful new therapy for this devastating disease.

Scientists have discovered a previously unknown mechanism by which apolipoprotein E, a molecule whose mutation is linked to Alzheimer's disease (AD), stimulates degradation of sticky amyloid beta (Aβ) protein within the brain. The research, published by Cell Press in the June 12 issue of the journal Neuron, may lead to a powerful new therapy for this devastating disease.

One of the primary characteristics of AD is the accumulation and deposition of neuron-damaging clumps of Aβ protein. Apolipoprotein E (ApoE), a cholesterol transport protein, is known to be a key regulator of brain Aβ levels, and it is likely that processes that regulate ApoE activity will influence Aβ deposition and clearance. "An isoform of ApoE, ApoE4, has been shown to confer dramatically increased risk for late-onset AD; however, the basis for this remains one of the major unanswered questions of disease pathogenesis," writes study author Dr. Gary E. Landreth from the Alzheimer Research Laboratory at Case Western Reserve University School of Medicine in Cleveland, Ohio.

Dr. Landreth and colleagues sought to unravel the link between ApoE, Aβ clearance in the brain, and an enhanced risk for AD. The researchers found that ApoE profoundly enhanced the intracellular and extracellular degradation of Aβ. This enhancement varied for different isoforms of ApoE with the ApoE4 isoform exhibiting an impaired ability to promote Aβ degradation when compared to other ApoE isoforms. The number of lipid molecules associated with ApoE was also critical to its ability to stimulate Aβ degradation. Activation of liver X receptors (LXRs) to enhance expression of lipidated ApoE significantly facilitated Aβ degradation. Importantly, use of an LXR agonist to increase lipidated forms of ApoE in a mouse model of AD resulted in reduced Aβ plaque levels and an improvement in contextual memory.

The results of this study document a major role for ApoE in the stimulation of Aβ degradation within the brain and highlight the importance of lipidation to the function of ApoE. This work also explains the previous observation that inactivation of a gene which helps the brain to process lipids (called Abca1) resulted in decreased levels of ApoE along with a seemingly paradoxical elevation of Aβ levels and plaque formation in mice. "Our data suggest that therapeutic agents that increase the levels of lipidated forms of ApoE, including LXR agonists, represent a potentially efficacious therapy for AD," concludes Dr. Landreth.

The researchers include Qingguang Jiang, Case Western Reserve University School of Medicine, Cleveland, OH; C.Y. Daniel Lee, Case Western Reserve University School of Medicine, Cleveland, OH; Shweta Mandrekar, Case Western Reserve University School of Medicine, Cleveland, OH; Brandy Wilkinson, Case Western Reserve University School of Medicine, Cleveland, OH; Paige Cramer, Case Western Reserve University School of Medicine, Cleveland, OH; Noam Zelcer, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA; Karen Mann, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; Bruce Lamb, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; Timothy M. Willson, GlaxoSmithKline, Discovery Research, Research Triangle Park, NC; Jon L. Collins, GlaxoSmithKline, Discovery Research, Research Triangle Park, NC; Jill C. Richardson, GlaxoSmithKline, New Frontiers Science Park, Harlow, UK; Jonathan D. Smith, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH; Thomas A. Comery, Wyeth Research, Princeton, NJ; David Riddell, Wyeth Research, Princeton, NJ ; David M. Holtzman, Washington University School of Medicine, St. Louis, MO; Peter Tontonoz, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA; and Gary E. Landreth, Case Western Reserve University School of Medicine, Cleveland, OH.


Story Source:

The above story is based on materials provided by Cell Press. Note: Materials may be edited for content and length.


Journal Reference:

  1. Qingguang Jiang, C.Y. Daniel Lee, Shweta Mandrekar, Brandy Wilkinson, Paige Cramer, Noam Zelcer, Karen Mann, Bruce Lamb, Timothy M. Willson, Jon L. Collins. ApoE Promotes the Proteolytic Degradation of Aβ. Neuron, 2008; 58 (5): 681 DOI: 10.1016/j.neuron.2008.04.010

Cite This Page:

Cell Press. "Mechanism Explains Link Between Apolipoprotein E And Alzheimer's Disease." ScienceDaily. ScienceDaily, 13 June 2008. <www.sciencedaily.com/releases/2008/06/080611135123.htm>.
Cell Press. (2008, June 13). Mechanism Explains Link Between Apolipoprotein E And Alzheimer's Disease. ScienceDaily. Retrieved September 21, 2014 from www.sciencedaily.com/releases/2008/06/080611135123.htm
Cell Press. "Mechanism Explains Link Between Apolipoprotein E And Alzheimer's Disease." ScienceDaily. www.sciencedaily.com/releases/2008/06/080611135123.htm (accessed September 21, 2014).

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