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 (A beta) precursor protein (APP) and presenilin (PS) 2 develop severe brain amyloidosis and cognitive deficits, two pathological hallmarks of Alzheimer's disease (A beta). One-year-old APP/PS2 mice with high brain levels of A beta and abundant A beta 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 A beta-like disturbances. Thus, IGF-I enhanced cognitive performance, decreased brain A beta load, increased the levels of synaptic proteins, and reduced astrogliosis associated to A beta plaques. The beneficial effects of IGF-I were associated to a significant increase in brain A beta 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 A beta/carrier protein complexes through the choroid plexus barrier, it seems that IGF-I favors elimination of A beta from the brain, supporting a therapeutic use of this growth factor in A beta. (c) 2005 Published by Elsevier Inc.