Insulin signaling in sporadic Alzheimer's disease.
Excessive production of beta-amyloid (Abeta) peptides from proteolytic cleavage of amyloid precursor protein is believed to play a central role in the pathogenesis of Alzheimer's disease (AD). In particular, accumulated intracellular Abeta is found in vulnerable neurons, and the soluble oligomers of Abeta peptides [also termed Abeta-derived diffusible ligands (ADDLs)] are highly toxic to neurons. Evidence shows that both extracellular and intracellular ADDLs can compromise insulin signaling. Extracellular ADDLs can bind to synapses and decrease membrane insulin receptors (IRs) through an insulin signaling-dependent mechanism. Intracellular Abeta inhibits IR signaling in neurons by interfering with the association between phosphoinositide-dependent kinase 1 and Akt1 to preclude Akt1 activation. Together, these findings suggest that agents that stimulate insulin signaling may have neuroprotective effects. Indeed, insulin and insulin sensitizers have been shown to improve cognitive and memory functions in animal models of AD, as well as in AD patients.
Liao
Francesca-Fang
FF
Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA. fliao@utmem.edu
Xu
Huaxi
H
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007328:Insulin / Q000494:pharmacology / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D018696:Neuroprotective Agents; D011972:Receptor, Insulin; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt