Scripps.edu - Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists’ ideas about Alzheimer’s disease, pointing to the liver instead of the brain as the source of the “amyloid” that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer’s prevention and treatment.
In their study, scientists used a mouse model for Alzheimer’s disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin - a cell membrane protein believed to contribute to the development of human Alzheimer’s.
“This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s,” said Scripps Research Professor Greg Sutcliffe, who led the study. “This could greatly simplify the challenge of developing therapies and prevention.”
In trying to help solve the Alzheimer’s puzzle, in the past few years Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation.
Sutcliffe’s gene hunt offered up good matches, or candidates, for each of the three disease modifier genes previously discovered by Case Western scientists, and one of these candidates - the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer’s disease - was of special interest to his team.
“The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid,” Sutcliffe explained. “Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer’s-like pathology.”
This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain.
To test this hypothesis, Sutcliffe’s team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. “We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice,” Sutcliffe said, “and one would predict in humans, too.”
The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.
“This characteristic of the drug is precisely why we chose to use it,” Sutcliffe explained. “Because it doesn’t penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease.”
The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured. The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer’s.
As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development. The abstract of the study is available here:
Reference: J. Gregor Sutcliffe, et al. Peripheral reduction of β-amyloid is sufficient to reduce brain αβ: implications for Alzheimer’s disease. Journal of Neuroscience Research. doi: 10.1002/jnr.22603
Scripps.edu - Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists’ ideas about Alzheimer’s disease, pointing to the liver instead of the brain as the source of the “amyloid” that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer’s prevention and treatment.
In their study, scientists used a mouse model for Alzheimer’s disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin - a cell membrane protein believed to contribute to the development of human Alzheimer’s.
“This unexpected finding holds promise for the development of new therapies to fight Alzheimer’s,” said Scripps Research Professor Greg Sutcliffe, who led the study. “This could greatly simplify the challenge of developing therapies and prevention.”
In trying to help solve the Alzheimer’s puzzle, in the past few years Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation.
Sutcliffe’s gene hunt offered up good matches, or candidates, for each of the three disease modifier genes previously discovered by Case Western scientists, and one of these candidates - the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer’s disease - was of special interest to his team.
“The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid,” Sutcliffe explained. “Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer’s-like pathology.”
This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain.
To test this hypothesis, Sutcliffe’s team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. “We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice,” Sutcliffe said, “and one would predict in humans, too.”
The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.
“This characteristic of the drug is precisely why we chose to use it,” Sutcliffe explained. “Because it doesn’t penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease.”
The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured. The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer’s.
As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development. The abstract of the study is available here:
Reference: J. Gregor Sutcliffe, et al. Peripheral reduction of β-amyloid is sufficient to reduce brain αβ: implications for Alzheimer’s disease. Journal of Neuroscience Research. doi: 10.1002/jnr.22603