Search

Levels of insulin-like growth factor I (IGF-I), a neuroprotective hormone, decrease in serum during aging, whereas amyloid-[beta] (A[beta]), which is involved in the pathogenesis of Alzheimer disease, accumulates in the brain. High brain A[beta] levels are found at an early age in mutant mice with low circulating IGF-I, and A[beta] burden can be reduced in aging rats by increasing serum IGF-I. This opposing relationship between serum IGF-I and brain A[beta] levels reflects the ability of IGF-I to induce clearance of brain A[beta], probably by enhancing transport of A[beta] carrier proteins such as albumin and transthyretin into the brain. This effect is antagonized by tumor necrosis factor-[alpha], a pro-inflammatory cytokine putatively involved in dementia and aging. Because IGF-I treatment of mice overexpressing mutant amyloid markedly reduces their brain A[beta] burden, we consider that circulating IGF-I is a physiological regulator of brain amyloid levels with therapeutic potential., Author(s): E. Carro [1]; J.L. Trejo [1]; T. Gomez-Isla [2]; D. LeRoith [3]; I. Torres-Aleman (corresponding author) [1] Insulin and insulin-like growth factor I (IGF-I) are structurally related circulating hormones. [...]

Increasing evidence indicates that circulating insulin-like growth factor I (IGF-I) acts as a peripheral neuroactive signal participating not only in protection against injury but also in normal brain function. Epidemiological studies in humans as well as recent evidence in experimental animals suggest that blood-borne IGF-I may be involved in cognitive performance. In agreement with observations in humans, we found that mice with low-serum IGF-I levels due to liver-specific targeted disruption of the IGF-I gene presented cognitive deficits, as evidenced by impaired performance in a hippocampal-dependent spatial-recognition task. Mice with serum IGF-I deficiency also have disrupted long-term potentiation (LTP) in the hippocampus, but not in cortex. Impaired hippocampal LTP was associated with a reduction in the density of glutamatergic boutons that led to an imbalance in the glutamatergic/GABAergic synapse ratio in this brain area. Behavioral and synaptic deficits were ameliorated in serum IGF-I-deficient mice by prolonged systemic administration of IGF-I that normalized the density of glutamatergic boutons in the hippocampus. Altogether these results indicate that liver-derived circulating IGF-I affects crucial aspects of mature brain function; that is, learning and synaptic plasticity, through its trophic effects on central glutamatergic synapses. Declining levels of serum IGF-I during aging may therefore contribute to age-associated cognitive loss.Molecular Psychiatry (2007) 12, 1118–1128; doi:10.1038/sj.mp.4002076; published online 11 September 2007 [ABSTRACT FROM AUTHOR]