Neuroscientists at Case Western Reserve University School of Medicine have made a dramatic breakthrough in their efforts to find a cure for Alzheimer’s disease. A recent edition of the journal Science will report on how Professor Gary Landreth and his team discovered that a cancer drug can quickly reverse Alzheimer’s symptoms in animal models. Within 72 hours of administration, the medication halved the number of plaque deposits closely associated with this degenerative brain disease. More, it saw the signs of cognitive and memory deficits disappear within the same short time period.
Bexarotene has been approved for the treatment of cancer by the U.S. Food and Drug Administration for more than a decade. These experiments explored whether the medication might also be used to help patients with Alzheimer’s disease, and the results were more than promising.
Alzheimer’s disease arises in large part from the body’s inability to clear naturally-occurring amyloid beta from the brain. In 2008 Case Western Reserve researcher Gary Landreth, PhD, professor of neurosciences, discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. Landreth, a professor of neurosciences in the university’s medical school, is the senior author of this study as well.
Landreth and his colleagues chose to explore the effectiveness of bexarotene for increasing ApoE expression. The elevation of brain ApoE levels, in turn, speeds the clearance of amyloid beta from the brain. Bexarotene acts by stimulating retinoid X receptors (RXR), which control how much ApoE is produced.
In particular, the researchers were struck by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of Alzheimer’s disease. The present view of the scientific community is that small soluble forms of amyloid beta cause the memory impairments seen in animal models and humans with the disease. Within six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent; even more impressive, the effect lasted as long as three days. Finally, this shift was correlated with rapid improvement in a broad range of behaviors in three different mouse models of Alzheimer’s.
This study identifies a link between the primary genetic risk factor for Alzheimer’s disease and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Possession of the ApoE4 gene greatly increases the likelihood of developing Alzheimer’s disease. Previously, the Landreth laboratory had shown that this form of ApoE was impaired in its ability of clear amyloid. The new work suggests that elevation of ApoE levels in the brain may be an effective therapeutic strategy to clear the forms of amyloid associated with impaired memory and cognition.
The Science study was co-authored by John R. Cirrito, Jessica L. Restivo, Whitney D. Goebel, Washington University School of Medicine; C.Y. Daniel Lee, Colleen Karlo, Adriana E. Zinn, Brad T. Casali, Case Western Reserve University School of Medicine; Donald A. Wilson, New York University School of Medicine, and Michael J. James, Kurt R. Brunden, Perelman School of Medicine, University of Pennsylvania.
The potential of this research to assist the 5.4 million Americans living with Alzheimer’s disease is immense. I commend Professor Landreth for this extraordinary research, and look forward to learning of additional progress as he takes it to clinical trials.