USC Researcher Discovers Role of Gene Variant Associated with
Alzheimer's Disease in Damage to Brain Circulation and Function
May 16, 2012
Highlights of this news release:
Los Angeles — A gene variant responsible for vascular damage to the brain is a promising new target for drug therapy to fight Alzheimer's disease and other neurodegenerative diseases, according to research published today by a University of Southern California (USC) scientist.
Berislav Zlokovic, Ph.D., deputy director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC, is the corresponding author on a study indicating that the gene variant apolipoprotein E4 (ApoE4), a major genetic risk factor for Alzheimer's disease, causes inflammation of blood vessels in the brains of genetically engineered mice. The gene variant allows entry of dangerous proteins that cause damage to the central nervous system. The research may be helpful not only for Alzheimer's patients but also for individuals with other neurological disorders associated with ApoE4, such as stroke and Down syndrome.
"Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," said Zlokovic, who is also professor and chair of the Department of Physiology and Biophysics at the Keck School. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system."
The research, "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A," was published May 16 in the journal Nature. Zlokovic conducted the research with first author Robert D. Bell, Ethan Winkler and other investigators from the University of Rochester.
The research is supported by the National Institute of Neurological Disorders and Stroke(NINDS; grant number R37NS34467) and the National Institute on Aging (NIA; grant numbers R37AG23084, RO1AG039452, and R37AG13956), both part of the National Institutes of Health (NIH).
Previous research has shown that a buildup of the toxic protein fragment beta amyloid constricts blood vessels in the brains of Alzheimer's patients. Zlokovic's team found that ApoE4 damages vessels independently of beta amyloid, leading to a breakdown of the blood-brain barrier, obstructing the flow of oxygen and nutrients into the brain and allowing accumulation in the brain of multiple neurotoxic products derived from the blood that are normally denied entry.
"Rather than trying to destroy amyloid plaques, this research indicates that therapies targeting the ApoE4 beta amyloid independent pathway may alleviate the development of neurodegenerative changes in the brain," Zlokovic said.
Apolipoprotein E helps to regulate levels and distribution of cholesterol and other lipids within the body and exists in three variations.
Two of three variants, ApoE2 and ApoE3, protect against Alzheimer's disease and heart disease or have no effect on either condition. The third variant, ApoE4, was seen to be ineffective in clearing cholesterol out of the body, but until now its role in the brain was not fully understood.
ApoE4 appears to weaken the blood-brain barrier by activating an inflammatory response in brain perivascular cells called pericytes, caused by an overabundance of an inflammatory molecule called cyclophilin A (CypA). CypA is controlled by ApoE2 and ApoE3 but is not affected by ApoE4, Zlokovic's team discovered.
The mice engineered to produce ApoE4 had five times the amount of CypA in their systems, activating an enzyme that destroyed protein components of the blood-brain barrier and thereby weakening it.
"The Nature paper shows there is a beta amyloid-independent pathway of neuronal degeneration that depends on vascular damage primarily within brain capillary circulation and breakdown of the blood-brain barrier," said Zlokovic. "This, in my opinion, is a very novel finding."
The findings highlight a growing awareness of a possible link between Alzheimer's-type dementia and stroke, and may open the door to therapies that improve vascular health in those predisposed to both conditions through high blood pressure, obesity and diabetes.
Article cited:
Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M.,
Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B.C. & Zlokovic, B.V. "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A." Nature. Published online May 16, 2012. doi:10.1038/nature11087
Contact: Leslie Ridgeway at (323) 442-2823 or lridgewa@usc.edu
- This research demonstrates that the gene variant ApoE4, a major genetic risk factor for Alzheimer's disease, damages the brain's vascular system and normal functions.
- ApoE4 allows an inflammatory molecule called cyclophilin A to weaken the blood-brain barrier, enabling accumulation of multiple toxic proteins in the brain.
- Other diseases of the brain associated with ApoE4 such as stroke, Down syndrome, poor outcome after brain trauma or intercerebral bleeding may benefit from therapies developed as a result of this discovery.
Los Angeles — A gene variant responsible for vascular damage to the brain is a promising new target for drug therapy to fight Alzheimer's disease and other neurodegenerative diseases, according to research published today by a University of Southern California (USC) scientist.
Berislav Zlokovic, Ph.D., deputy director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC, is the corresponding author on a study indicating that the gene variant apolipoprotein E4 (ApoE4), a major genetic risk factor for Alzheimer's disease, causes inflammation of blood vessels in the brains of genetically engineered mice. The gene variant allows entry of dangerous proteins that cause damage to the central nervous system. The research may be helpful not only for Alzheimer's patients but also for individuals with other neurological disorders associated with ApoE4, such as stroke and Down syndrome.
"Understanding the role of ApoE4 in Alzheimer's disease may be one of the most important avenues to a new therapy," said Zlokovic, who is also professor and chair of the Department of Physiology and Biophysics at the Keck School. "Our study shows that ApoE4 triggers a cascade of events that damages the brain's vascular system."
The research, "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A," was published May 16 in the journal Nature. Zlokovic conducted the research with first author Robert D. Bell, Ethan Winkler and other investigators from the University of Rochester.
The research is supported by the National Institute of Neurological Disorders and Stroke(NINDS; grant number R37NS34467) and the National Institute on Aging (NIA; grant numbers R37AG23084, RO1AG039452, and R37AG13956), both part of the National Institutes of Health (NIH).
Previous research has shown that a buildup of the toxic protein fragment beta amyloid constricts blood vessels in the brains of Alzheimer's patients. Zlokovic's team found that ApoE4 damages vessels independently of beta amyloid, leading to a breakdown of the blood-brain barrier, obstructing the flow of oxygen and nutrients into the brain and allowing accumulation in the brain of multiple neurotoxic products derived from the blood that are normally denied entry.
"Rather than trying to destroy amyloid plaques, this research indicates that therapies targeting the ApoE4 beta amyloid independent pathway may alleviate the development of neurodegenerative changes in the brain," Zlokovic said.
Apolipoprotein E helps to regulate levels and distribution of cholesterol and other lipids within the body and exists in three variations.
Two of three variants, ApoE2 and ApoE3, protect against Alzheimer's disease and heart disease or have no effect on either condition. The third variant, ApoE4, was seen to be ineffective in clearing cholesterol out of the body, but until now its role in the brain was not fully understood.
ApoE4 appears to weaken the blood-brain barrier by activating an inflammatory response in brain perivascular cells called pericytes, caused by an overabundance of an inflammatory molecule called cyclophilin A (CypA). CypA is controlled by ApoE2 and ApoE3 but is not affected by ApoE4, Zlokovic's team discovered.
The mice engineered to produce ApoE4 had five times the amount of CypA in their systems, activating an enzyme that destroyed protein components of the blood-brain barrier and thereby weakening it.
"The Nature paper shows there is a beta amyloid-independent pathway of neuronal degeneration that depends on vascular damage primarily within brain capillary circulation and breakdown of the blood-brain barrier," said Zlokovic. "This, in my opinion, is a very novel finding."
The findings highlight a growing awareness of a possible link between Alzheimer's-type dementia and stroke, and may open the door to therapies that improve vascular health in those predisposed to both conditions through high blood pressure, obesity and diabetes.
Article cited:
Bell, R.D., Winkler, E.A., Singh, I., Sagare, A.P., Deane, R., Wu, Z., Holtzman, D.M.,
Betsholtz, C., Armulik, A., Sallstrom, J., Berk, B.C. & Zlokovic, B.V. "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A." Nature. Published online May 16, 2012. doi:10.1038/nature11087
Contact: Leslie Ridgeway at (323) 442-2823 or lridgewa@usc.edu
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