Abstract
Amyloid β protein (Aβ) may play a causal role in Alzheimer's disease. Previous work has shown that the learning and memory deficits that develop with aging in SAMP8 mice, a strain that overproduces Aβ, can be reversed with i.c.v. injections of an Aβ antisense phosphorothiolate oligonucleotide (Olg). Here, we showed that Olg radioactively labeled with 32P (P-Olg) was transported intact across the blood-brain barrier (BBB) of mice by a saturable system, termed oligonucleotide transport system-1 (OTS-1). Multiple-time regression analysis found a blood-to-brain unidirectional influx rate for P-Olg of 1.4 ± 0.39 μl/g-min and capillary depletion showed that P-Olg completely crossed the BBB to enter the parenchymal space of the brain. P-Olg was also shown to enter the cerebrospinal fluid. Transport was especially high into the hippocampus, with the percentage of the i.v. dose taken 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 reversed the learning and memory deficits of aged SAMP8 mice. These studies show for the first time that phosphorothiolate oligonucleotides can be delivered to the brain in effective doses by intravenous administration.
Footnotes
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Send reprint requests to: Dr. John E. Morley, Saint Louis University Health Sciences Center, Division of Geriatric Medicine, 1402 S. Grand Blvd., Room M238, St. Louis, MO 63104. E-mail:morley{at}slu.edu
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This study was supported by Veterans Affairs Merit Review, R0-1 MH54979, and R0-1 NS41863.
- Abbreviations:
- CNS
- central nervous system
- BBB
- blood-brain barrier
- Aβ
- amyloid β protein
- APP
- amyloid precursor protein
- Olg
- phosphorothiolate oligonucleotide
- P-Olg
- oligonucleotide radioactively labeled with 32P
- LR-BSA
- lactated Ringer's solution containing 1% by volume of bovine serum albumin
- Expt
- exposure time
- Vi
- distribution volume in brain att = 0
- %Inj/g
- percentage of the dose injected i.v. taken up by each gram of brain
- CSF
- cerebrospinal fluid
- PE
- polyethylene
- OTS-1
- oligonucleotide transport system-1
- ANOVA
- analysis of variance
- Received January 3, 2001.
- Accepted February 16, 2001.
- U.S. Government
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