The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease.
Cellular and molecular processes leading to abnormal accumulation of beta amyloid in the brain are slowly being uncovered. A potential involvement of insulin and insulin-like growth factor I (IGF-I) in this plausible pathogenic process in Alzheimer's disease has recently been proposed. Evidence favoring this idea stems from the ability of both hormones to stimulate beta amyloid release from neurons as well as by the stimulatory effect that IGF-I exerts on brain amyloid clearance. In addition, insulin and IGF-I levels are altered in Alzheimer's patients and, probably in close association to these changes, cell sensitivity towards insulin--and possibly also IGF-I--is decreased in these patients. We now review evidence that disturbed insulin/IGF-I signaling to brain cells, initiated at the level of the blood-brain barriers is probably instrumental in development of brain amyloidosis. Furthermore, insulin and IGF-I are potent neuroprotective factors and can regulate levels of phosphorylated tau, a major component of neurofibrillary tangles found in Alzheimer's brains. Therefore, a decrease in trophic support to neurons together with increased tau phosphorylation will follow loss of sensitivity towards insulin and IGF-I. Altogether, this supports the notion that a single pathogenic event, i.e., brain resistance to insulin/IGF-I, accounts for neuronal atrophy/death, tangle formation and brain amyloidosis typical of Alzheimer's pathology.
Carro
Eva
E
Laboratory of Neuroendocrinology, Cajal Institute, CSIC, Avenida Doctor Arce 37, Madrid ES 28002, Spain.
Torres-Aleman
Ignacio
I
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D006801:Humans; D007328:Insulin / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000502:physiology*; D008954:Models, Biological
D016229:Amyloid beta-Peptides; D007328:Insulin; D007334:Insulin-Like Growth Factor I