Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis.

Transgenic mice expressing mutant forms of both amyloid-beta (Abeta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (AD). One-year-old APP/PS2 mice with high brain levels of Abeta and abundant Abeta plaques show disturbances in spatial learning and memory. Treatment of these deteriorated mice with a systemic slow-release formulation of insulin-like growth factor I (IGF-I) significantly ameliorated AD-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain Abeta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to Abeta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain Abeta complexed to protein carriers such as albumin, apolipoprotein J or transthyretin. Since levels of APP were not modified after IGF-I therapy, and in vitro data showed that IGF-I increases the transport of Abeta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of Abeta from the brain, supporting a therapeutic use of this growth factor in AD.