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

• Published in: Biochemical pharmacology 2008-03, Vol.75 (5), p.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: Article
• Language: English
• Subjects: Adult and adolescent clinical studies; Alzheimer's disease; Biological and medical sciences; Clearance; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; IGF-1; Medical sciences; Neurology; Organic mental disorders. Neuropsychology; Pharmacology. Drug treatments; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Tau; Tg2576
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2007.11.001

Increasing beta-amyloid (Aβ) 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 Aβ clearance by facilitating transport of Aβ 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 Aβ acutely, with reduction in plaque pathology after chronic treatment. Thus Aβ 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 Aβ 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 Aβ. 5-day treatment of young Tg2576 mice with IGF-1 produced robust elevations of IGF-1 levels in plasma, but no effects on Aβ 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 Aβ (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 Aβ 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.