Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols

Jason Pitt, Michael Thorner, David Brautigan, Joseph Larner, William L. Klein*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

Alzheimer's disease (AD) is a progressive dementia that correlates highly with synapse loss. This loss appears due to the synaptic accumulation of toxic Aβ oligomers (ADDLs), which damages synapse structure and function. Although it has been reported that oligomer binding and toxicity can be prevented by stimulation of neuronal insulin signaling with PPARγ agonists, these agonists have problematic side effects. We therefore investigated the therapeutic potential of chiro-inositols, insulin-sensitizing compounds safe for human consumption. Chiro-inositols have been studied extensively for treatment of diseases associated with peripheral insulin resistance, but their insulin mimetic function in memory-relevant central nervous system (CNS) cells is unknown. Here we demonstrate that mature cultures of hippocampal neurons respond to D-chiro-inositol (DCI), pinitol (3-O-methyl DCI), and the inositol glycan INS-2 (pinitol β-1-4 galactosamine) with increased phosphorylation in key upstream components in the insulin-signaling pathway (insulin receptor, insulin receptor substrate-1, and Akt). Consistent with insulin stimulation, DCI treatment promotes rapid withdrawal of dendritic insulin receptors. With respect to neuroprotection, DCI greatly enhances the ability of insulin to prevent ADDL-induced synapse damage (EC50 of 90 nM). The mechanism comprises inhibition of oligomer binding at synapses and requires insulin/ IGF signaling. DCI showed no effects on Aβ oligomerization. We propose that inositol glycans and DCI, a compound already established as safe for human consumption, have potential as AD therapeutics by protecting CNS synapses against Aβ oligomers through their insulin mimetic activity.

Original languageEnglish (US)
Pages (from-to)199-207
Number of pages9
JournalFASEB Journal
Volume27
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • Cell culture
  • Dementia
  • Neurodegeneration
  • Therapeutics

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Fingerprint Dive into the research topics of 'Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols'. Together they form a unique fingerprint.

Cite this