Abstract

Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid- (A), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain A levels are found at an early age in mutant mice with low circulating IGF-I, and A burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain A levels reflects the ability of IGF-I to induce clearance of brain A, probably by enhancing transport of A carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-, a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain A burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential.