Amyloid beta (red areas-left image) peptides clear from the brain of an Alzheimer's mouse after three days of treatment with a cancer drug (right image). Souce: AAAS/Science
Neuroscientists at Case Western Reserve University School of Medicine have just reported a breakthrough in their efforts to find a cure for Alzheimer’s disease (AD). The findings, published in the journal of Science, show that the administration of a drug in mice appears to quickly reverse the pathological, cognitive, and memory deficits caused by the onset of AD.
The drug with this potential: Bexarotene. Bexarotene has been FDA approved for the treatment of a type of skin cancer for more than a decade. The Landreth lab at Case Western explored whether this medication would also be useful in treating patients with Alzheimer’s disease. The results the lab obtained were more than promising.
Before I delve into their findings, it is important to understand basic AD pathology. AD arises in large part from the body’s inability to clear naturally-occurring beta amyloid from the brain. In 2008, members of the Landreth lab discovered that the main cholesterol carrier in the brain, Apolipoprotein E (ApoE), facilitated the clearance of the amyloid beta proteins. So, they decided to explore the effectiveness of bexarotene for increasing ApoE expression. This was based off the idea that elevation of ApoE levels speeds the clearance of amyloid beta from the brain and bexarotene acts by stimulating the receptors which control how much ApoE is produced.
The researchers were stunned by the speed with which bexarotene improved memory deficits and behavior even as it also acted to reverse the pathology of AD. Today, the scientific community agrees that small soluble forms of amyloid beta cause the memory impairments displayed by animal models and humans with the disease. Within just six hours of administering bexarotene, however, soluble amyloid levels fell by 25 percent. Even more astonishing was the fact that the effect lasted three days and was correlated with rapid improvement in a broad range of behaviors in three different mouse models of AD.
Researchers found that more than half of the plaques had been cleared within 72 hours. Ultimately, the reductions totaled 75 percent. The research team believes that the bexarotene reprogrammed the brain’s immune system to “eat” the amyloid deposit which demonstrates that the drug addresses the amount of both soluble and deposited forms of amyloid beta within the brain and thus, reverses the pathological features of the disease in mice.
This study also identifies a link between the primary genetic risk factor for AD and a potential therapy to address it. Humans have three forms of ApoE: ApoE2, ApoE3, and ApoE4. Carriers of the ApoE4 gene are at an increased risk for developing Alzheimer’s. The Landreth lab has previously shown that the e4 variant was impaired in its ability to clear amyloid. These new results suggest that elevation of ApoE levels may be an effective strategy to clear the forms of amyloid associated with impaired memory and cognition.
The Landreth lab is in the very early stages of beginning the translation to clinical trials of the drug. One can only hope that this drug has some effect on amyloid clearance in humans similar to that seen in the mouse models.
It is important to note that while this study appears to be a dramatic breakthrough in the efforts for finding a cure for AD, the results were only found in mouse models of the disease. There have been 300 reports of treatments that cure Alzheimer’s in mice since 1995. Unfortunately the number of cures in humans in 2012 still reads zero. This is because while the mouse model holds genetic mutations that cause mice to display similar cognitive impairments, it is an imperfect model for a true AD patient. No single mouse replicates all the symptoms associated with human Alzheimer’s disease. The exact cause and progression of AD remains unknown, which makes finding a cure difficult when we still haven’t even unwrapped the actual problem. Lastly, if this drug were to be effective in humans, it still would not help the patients in the advanced stages of Alzheimer’s, whose memory loss and impaired cognitive abilities are the result of neuronal death. Bexarotene can reduce levels of amyloid beta, but unfortunately it cannot reverse cell death.
Point being, while these new results hold promise for the future of AD, we must not forget that there is much more to be discovered about the cause and progression of this terrible disease.
Resource: Cramer, et al. ApoE-Directed Therapeutics Rapidly Clear Beta-Amyloid and Reverse Deficits in AD Mouse Models. Science (9 February 2012) DOI: 10.1126/science.1217697