February 17, 2012

By: JEFF EVANS, Internal Medicine News Digital Network

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FROM SCIENCE

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A pharmacotherapeutic approach that harnesses the amyloid-beta clearing effects of the apolipoprotein E gene while also activating microglia to clear amyloid plaques from the brains of mouse models of Alzheimer’s disease could become a new treatment strategy to test clinically.

The protein product of the APOE gene – the most influential genetic risk factor for late-onset Alzheimer’s disease in humans – normally acts to help build high-density lipoprotein (HDL) particles that promote the degradation of soluble forms of amyloid-beta, which is thought by many researchers to cause the cognitive dysfunction associated with Alzheimer’s. However, efforts that seek to induce the expression of the APOE gene must also ensure that its protein product is lipidated by associated proteins in order for it to clear soluble amyloid-beta.

Gary E. Landreth, PhD.

Paige E. Cramer and Gary E. Landreth, Ph.D., of Case Western Reserve University, Cleveland, and their colleagues took that approach in experiments by inducing the expression of APOE in mouse models of Alzheimer’s disease with the retinoid X receptor agonist bexarotene (Targretin). The drug already is approved by the Food and Drug Administration for the treatment of cutaneous T-cell lymphoma; it is known to cross the blood-brain barrier and has a favorable safety profile.

The investigators used an agonist of the retinoid X receptor (RXR) because the receptor increases the expression of APOE and the lipid transporters ABCA1 and ABCG1 while also stimulating the secretion of highly lipidated HDL particles that are necessary for the clearance of soluble amyloid-beta. RXR agonists such as bexarotene also convert microglia and macrophages into an alternative activation state that helps to clear amyloid-beta plaques.

Unlike interventional approaches to Alzheimer’s therapy that have used vaccines or inhibitors of beta- and gamma-secretase, Dr. Landreth and his colleagues stimulated the normal, physiological clearance mechanisms for soluble amyloid-beta and amyloid-beta plaques.

“There’s no precedent for this,” Dr. Landreth said in an interview.

Photo (c)Science/AAAS Significantly fewer amyloid-beta plaques (red) remain in the cortex of a 6-month-old mouse model of Alzheimer's disease after a 14-day period of treatment with bexarotene (left image) than after placebo treatment (right).

Dr. Landreth emphasized that the oncologically effective dose that they used in the experiments is “way too high to treat Alzheimer’s disease or other CNS diseases,” noting that “it may be unsafe to administer this drug to an AD patient at anywhere near the dosages we’ve reported.”

Within 24 hours of giving bexarotene to transgenic mice expressing mutations in several genes known to be associated with early-onset Alzheimer’s in humans, the investigators found that brain interstitial fluid levels of amyloid-beta had dropped by 25%, followed by a return to baseline by 84 hours. However, the drug had no effect on amyloid-beta levels in mice bred without APOE, which indicated that the clearance of amyloid-beta required APOE (Science 2012 Feb. 9 [doi:10.1126/science.1217697]).

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