A research team led by Robert Nagele, PhD, of the New Jersey Institute for Successful Aging (NJISA) at the University of Medicine and Dentistry of New Jersey (UMDNJ)-School of Osteopathic Medicine, has demonstrated that the anti-atherosclerosis drug darapladib can significantly reduce leaks in the blood brain barrier. This finding potentially opens the door to new therapies to prevent the onset or the progression of Alzheimer's disease.
Writing in the Journal of Alzheimer's Disease (currently in press), the researchers describe findings involving the use of darapladib in animal models that had been induced to develop diabetes mellitus and hypercholesterolemia (DMHC), which are considered to be major risk factors for Alzheimer's disease.
"Diabetes and hypercholesterolemia are associated with an increased permeability of the blood-brain barrier, and it is becoming increasingly clear that this blood-brain barrier breakdown contributes to neurodegenerative diseases such as Alzheimer's," Nagele said. "Darapladib appears to be able to reduce this permeability to levels comparable to those found in normal, non-DMHC controls, and suggests a link between this permeability and the deposition of amyloid peptides in the brain."
The study involved 28 animal (pig) models that were divided into three groups -- DMHC animals treated with a 10 mg/day dose of darapladib; DMHC animals that received no treatment; and non-DMHC controls. Post-mortem analysis of the brains of the darapladib-treated animals showed significant decreases in blood-brain barrier leakage and in the density of amyloid-positive neurons in the cerebral cortices. Interestingly, the amyloid peptides that leaked into the brain tissue were found almost exclusively in the pyramidal neurons of the cerebral cortex, one of the earliest pathologies of the development of Alzheimer's disease.
"Because our results suggest that these metabolic disorders can trigger neurodegenerative changes through blood-brain barrier compromise, therapies -- such as darapladib -- that can reduce vascular leaks have great potential for delaying the onset or slowing the progression of diseases like Alzheimer's," said the study's lead author, Nimish Acharya, PhD, of the NJISA and the UMDNJ-Graduate School of Biomedical Sciences. "The clinical, caregiving and financial impact of such an effect cannot be overestimated."
This study was supported by funding from GlaxoSmithKline through an industry-academic alliance via the Alternative Drug Discovery Initiative with the University of Pennsylvania School of Medicine.
Materials provided by University of Medicine and Dentistry of New Jersey (UMDNJ). Note: Content may be edited for style and length.
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