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.
Carro
E
E
Laboratory of Neuroendocrinology, Cajal Institute, CSIC, Avda. Dr. Arce 37, 28002 Madrid. Spain.
Trejo
J L
JL
Gerber
A
A
Loetscher
H
H
Torrado
J
J
Metzger
F
F
Torres-Aleman
I
I
D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000686:Amyloidosis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects; D001927:Brain Diseases / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D007150:Immunohistochemistry / Q000379:methods; D007334:Insulin-Like Growth Factor I / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D013037:Spatial Behavior / Q000187:drug effects
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D007334:Insulin-Like Growth Factor I