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Cancer Drug Clears Amyloid Beta, Improves Behavior in Alzheimer Disease Mice

ARTICLE IN BRIEF

DR. GARY E. LANDRETH

: “Weve shown that if we can use RXR agonists, we can clear soluble amyloid from the brain beginning at six hours, and basically for as long as we can look. We believe it is the soluble forms that correlate with the behavioral defi cits, and by clearing those, we restore behavioral defi cits, and regenerate normal network behavior in the brain.”

In both wild-type and Alzheimer disease model mice, bexarotene, an FDA-approved drug for cancer treatment, both rapidly increased expression of apolipoprotein E and promoted clearance of soluble amyloid beta by 30 percent, beginning within hours of administration. In addition, acute treatment improved the animals' abilities in a range of behavioral tests.

An FDA-approved cancer drug boosts brain apolipoprotein E (APOE), rapidly clears amyloid beta (Abeta), and improves behavior in a mouse model of Alzheimer disease (AD), according to a study published in the Feb. 9 online edition of the journal Science. The study strongly links two major risk factors for sporadic AD and opens the way for clinical trials exploiting this new strategy.

“This represents new biology,” said principal investigator Gary E. Landreth, PhD, professor of neurosciences and neurology and director of the Alzheimer Research Laboratory at Case Western Reserve University in Cleveland.

The link that Dr. Landreth has elucidated “is that an unappreciated function of APOE is to promote and accelerate the normal proteolytic clearance of amyloid.”

APOE is the scaffold for the formation of high-density lipoprotein particles, he explained, and these particles are the principle mechanism for lipid trafficking in the brain. The Abeta peptide binds to APOE, ultimately leading to its degradation.

“Abeta is made at a prodigious rate, all the time, in our brain,” he said. The maximal rate of clearance exceeds the production rate, but not by much, “so a small perturbation in the clearance mechanisms will lead to the accumulation of Abeta in the brain. As we age, these intrinsic clearance mechanisms become less efficient.” Recent work has shown that in AD patients, clearance is reduced by as much as 30 percent.

“The idea is that if we can elevate APOE in the brain, we should promote Abeta clearance,” Dr. Landreth said.

THE EXPERIMENTAL PROTOCOLS

To do so, his lab has explored how transcription of APOE is regulated. His work has shown that the APOE gene is turned on by the coordinated action of two nuclear receptors, each of which must bind to a “retinoid X receptor” (RXR) to become activated. When it binds an agonist, the receptor-RXR complex becomes activated and increases APOE transcription.

“We figured if we took an RXR agonist, we could drive this more robustly,” Dr. Landreth said. The cell has its own RXR agonists, but there are exogenous ones as well, including bexarotene, which not only has FDA approval for treatment of cutaneous T-cell lymphoma cancer, but also is orally delivered and crosses the blood-brain barrier.

Dr. Landreth's group showed that in both wild-type and Alzheimer disease model mice, bexarotene rapidly increased expression of APOE, and promoted clearance of soluble Abeta by 30 percent, beginning within hours of administration. No effect was seen in an Abeta knockout mouse. “This argues forcefully that the clearance of soluble forms of Abeta in the brain are APOE-dependent, and can be actively manipulated by elevating APOE levels,” he said.

His group also found that in an AD mouse with significant plaque accumulation, 30 percent of plaques were removed after 72 hours of treatment, and 50 percent after seven days. “I think this is unprecedented,” he said. As part of the drug's effect, microglia became activated and increased their level of phagocytosis of amyloid.

Dr. Landreth noted that with longer-term treatment, the rate of drug metabolism increases, causing plaque levels to rise again over the course of several months. He is currently investigating this phenomenon further.

Acute treatment improved the animals' abilities in a range of behavioral tests, and these effects were undiminished in mice receiving chronic treatment, even as their plaques returned, suggesting the possibility, Dr. Landreth said, that “plaques don't matter.” In a conditioned fear experiment, AD mice learn shock avoidance less well than their wild-type counterparts. “But after seven days of treatment, we can totally reverse this phenotype.” The treatment worked at six months, as mice are beginning to display the loss of learning behavior, and even at 11 months, when their symptoms are more florid.

Treatment also improved nesting behavior, a manifestation of social behavior in mice. At one year, Dr. Landreth explained, AD mice do not form nests normally. “We put them on the drug, and within 72 hours, we can almost completely reverse this behavioral deficit.”

Improvements in cognitive and social behaviors were accompanied by amelioration of aberrant activity of two neuronal circuits — measured by local field potentials — distinguished by their frequency. Activity of both so-called beta and gamma circuits are depressed in AD mice at 14 months, changes linked to odor-guided behavior and discrimination of odors.

DR. DOUGLAS GALASKO

: “Dr Landreths study shows increased clearance of Abeta related to changes in APOE lipidation, so these mechanisms can certainly be explored further in animal models even as early clinical trials go forward in humans. The toxicity of currently available drugs such as bexarotene will need to be closely examined in human studies.”

“If we put these guys on drugs for 72 hours, we can completely reverse these network activity deficits,” he said.

“We've shown that if we can use RXR agonists, we can clear soluble amyloid from the brain beginning at six hours, and basically for as long as we can look. We believe it is the soluble forms that correlate with the behavioral deficits, and by clearing those, we restore behavioral deficits, and regenerate normal network behavior in the brain,” Dr. Landreth concluded. “Furthermore, we are simply helping Mother Nature do what she does anyway. We are stimulating physiological clearance mechanisms by elevating APOE.”

He noted that a key difference between the APOE-e4 allele, which predisposes to AD, and the APOE-e2 and –e3 alleles, is that “APOE-e2 and e3 really clinch that HDL particle,” while the protein made from the –e4 allele leads to smaller, less stable lipoprotein particles, which therefore can carry less a-beta. Boosting the total amount of –e4 should overcome that, he suggested. “If you have an e4 allele, this may be just the drug for you, because the more you have, the better off you'll be clearing a-beta.”

Because it links regulation of amyloid accumulation with the APOE gene, he said, “This ties together the major risk factors for sporadic late-onset forms of AD. If we can target APOE at a transcriptional level, I think we may have an interesting therapeutic.”

The next step, he said, was to approach the FDA to conduct a phase 1 trial in healthy volunteers, to see if bexarotene increases APOE levels in CSF. If so, he said, a phase 2 trial would be the next step. He noted that the likely dose would be “an order of magnitude below” the dose approved for chemotherapy. Because the goal would be to keep APOE elevated, but not constantly increasing, the drug may be effective given only several times per month, he suggested.

EXPERT COMMENTARY

“It is a fascinating and remarkable result,” said Douglas Galasko, MD, professor of neuroscience at the University of California, San Diego. “It is a novel mechanism of action that I think should be considered strongly in relation to Alzheimer's disease.”

Dr. Galasko noted, however, that one of the problems with the rodent models of AD is that plaque clearance can be brought about by a large number of agents, including even ones that act peripherally, “so it may be easier to get rid of amyloid in mice than in humans.”

“Dr Landreth's study shows increased clearance of Abeta related to changes in APOE lipidation, so these mechanisms can certainly be explored further in animal models even as early clinical trials go forward in humans,” he said. “The toxicity of currently available drugs such as bexarotene will need to be closely examined in human studies.”

Dave Morgan, PhD, director of Basic Neuroscience Research at the University of South Florida College of Medicine in Tampa, noted that two things were particularly intriguing in the study. “First, given how rapidly and substantially it is reducing amyloid loads, the treatment is almost certainly removing preexisting amyloid deposits,” which no other putative AD treatment has been shown to do, except for antibodies. “Most of us in the field think the most useful agents will those that remove deposits,” rather than just slow new deposition. Second, Dr. Morgan said, this was something Dr. Landreth predicted would happen with this compound, based on his understanding of APOE regulation. “He wasn't just randomly poking holes in nature and seeing what falls out. That's a real ‘hats off’ to him.”

REFERENCE:

• Cramer PE, Cirrito JR, Landreth GE, et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 2012; E-pub 2012 Feb 9.