Insulin Signaling in Sporadic Alzheimer’s Disease

Francesca-Fang Liao^1* and Huaxi Xu^2*

¹ Department of Pharmacology, University of Tennessee Health Science Center, 874 Union Avenue, Memphis, TN 38163, USA.
² Neurodegenerative Disease Research Program, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

Abstract: Excessive production of β-amyloid (Aβ) 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 Aβ is found in vulnerable neurons, and the soluble oligomers of Aβ peptides [also termed Aβ-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 Aβ 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.

* Corresponding authors. E-mail, fliao{at}utmem.edu (F.-F.L.); xuh{at}burnham.org (H.X.)

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