Delivery across the blood-brain barrier of antisense directed against amyloid beta: Reversal of learning and memory deficits in mice overexpressing amyloid precursor protein

Amyloid beta protein (A beta) may play a causal role in Alzheimer's disease . Previous work has shown that the learning and memory deficits that develo p with aging in SAMP8 mice, a strain that overproduces A beta, can be rever sed with i.c.v. injections of an AP antisense phosphorothiolate oligonucleo tide (Olg), Here, we showed that Olg radioactively labeled with P-32 (P-Olg ) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multip le-time regression analysis found a blood-to-brain unidirectional influx ra te for P-Olg of 1.4 +/- 0.39 mul/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brai n. P-Olg was also shown to enter the cerebrospinal fluid. Transport was esp ecially high into the hippocampus, with the percentage of the i.v. dose tak en up by each gram of brain (0.865 +/- 0.115%) being about 1/100 of the i.c .v. dose. An i.v. dose of Olg 100 times that of the effective i.c.v. dose r eversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be deli vered to the brain in effective doses by intravenous administration.