Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models.
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.
Lanz
Thomas A
TA
CNS Discovery, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, United States. thomas.a.lanz@pfizer.com
Salatto
Christopher T
CT
Semproni
Anthony R
AR
Marconi
Michael
M
Brown
Tracy M
TM
Richter
Karl E G
KE
Schmidt
Kari
K
Nelson
Frederick R
FR
Schachter
Joel B
JB
D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002460:Cell Line; D004285:Dogs; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D018995:Myosin Heavy Chains