Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models

• Published in: Biochemical pharmacology Vol. 75; no. 5; pp. 1093 - 1103
• Main Authors: Lanz, Thomas A, Salatto, Christopher T, Semproni, Anthony R, Marconi, Michael, Brown, Tracy M, Richter, Karl E G, Schmidt, Kari, Nelson, Frederick R, Schachter, Joel B
• Format: Journal Article
• Language: English
• Published: England 01-03-2008
• Subjects: Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Peptides - metabolism; Animals; Brain - drug effects; Brain - metabolism; Cell Line; Dogs; Female; Humans; Insulin-Like Growth Factor I - pharmacokinetics; Insulin-Like Growth Factor I - pharmacology; Male; Mice; Mice, Transgenic; Myoblasts - cytology; Myoblasts - drug effects; Myoblasts - metabolism; Myosin Heavy Chains - metabolism; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recombinant Proteins - blood; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - pharmacology
• ISSN: 1873-2968

Increasing beta-amyloid (Abeta) clearance may alter the course of Alzheimer's disease progression and attenuate amyloid plaque pathology. Insulin-like growth factor I (IGF-1) augmentation has been suggested to increase Abeta clearance by facilitating transport of Abeta out of the brain. The availability of safe agents that increase IGF-1 levels therefore makes IGF-1 elevation an attractive target for disease modifying therapy in AD. The present series of studies sought to replicate published paradigms in which peripheral IGF-1 administration lowered brain Abeta acutely, with reduction in plaque pathology after chronic treatment. Thus Abeta levels were measured in several animal models following treatments that elevated IGF-1. Administration of IGF-1 to young or old rats for up to 3 days had no effect on Abeta levels in brain, CSF, or plasma. In adult beagles, 4 days of dosing with the growth hormone secretagogue, CP-424391, doubled baseline plasma IGF-1 levels, yet failed to alter CSF or plasma Abeta. 5-day treatment of young Tg2576 mice with IGF-1 produced robust elevations of IGF-1 levels in plasma, but no effects on Abeta were detected in brain, CSF, or plasma. Finally, 11-month-old Tg2576 mice were implanted with subcutaneous minipumps delivering IGF-1 for 1 month. No significant changes in Abeta (by ELISA or Western blot), plaque pathology, or phospho-tau epitopes were detected. These results do not demonstrate acute or chronic actions of peripherally administered IGF-1 on Abeta levels or the phosphorylation state of tau and therefore do not suggest any disease-modifying benefits of IGF-1 restorative therapy for AD through these mechanisms.