Apo E and Clusterin Suppress Alzheimer's Plaque Formation

Research into the biochemical basis for Alzheimer's disease has found that two proteins, apoplipoprotein E (Apo E) and clusterin, suppress the metabolism that results in the disposition of amyloid plaques in the brain and that the effect appears to be synergistic.

Apo E is a protein found in very low-density, low-density, and high-density lipoproteins. With a molecular weight of 33,000, Apo E is involved in binding lipoprotein complexes to the low-density lipoprotein receptor. Apo E is found in the human Apo C-II gene cluster, and a variant of Apo E has been associated with an increased risk for Alzheimer's disease.

Clusterin is a vertebrate glycoprotein, the exact function of which is not yet clear. Clusterin expression is complex, appearing as different forms in different cell compartments. One set of proteins is directed for secretion, and other clusterin species are expressed in the cytoplasm and nucleus.

Investigators at the Washington University School of Medicine (St. Louis, MO, USA; www.wustl.edu) genetically engineered lines of mice to lack the genes for apo E, clusterin, or both proteins. Animals were examined at different ages to determine the amount of plaque formation in the brain.

They reported in the January 22, 2004, issue of Neuron that the mice lacking both proteins displayed earlier onset and markedly increased amyloid beta protein levels and amyloid deposition. Both groups of mice lacking only one of the proteins had elevated cerebrospinal fluid and brain interstitial fluid amyloid beta, as well as significant differences in the elimination half-life of interstitial fluid amyloid beta measured by in vivo microdialysis.

"This is one of the first demonstrations in living animals that these proteins affect amyloid clearance,” explained Dr. David H. Holtzman, professor of neurology at the Washington University Medical School. "Our findings suggest it is worthwhile to explore the use of drugs or therapies to alter or perhaps increase the expression of these proteins as a potential treatment for Alzheimer's disease.”



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