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

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 (EC(50) 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.

Una revisión de los avances en la terapéutica de la enfermedad de Alzheimer: estrategia frente a la proteína β-amiloide

“…Además, el pinitol actúa como un sensibilizador de insulina. El compuesto modula la ␥-secretasa reduciendo la producción de ␤A, mientras que no afecta la escisión del sustrato de Notch-␥-secretasa 32,33 . Se ha indicado que el compuesto mejora el déficit de la función y la memoria cognitiva en modelos preclínicos de neuropatología de la EA 33 .…”

“…El compuesto modula la ␥-secretasa reduciendo la producción de ␤A, mientras que no afecta la escisión del sustrato de Notch-␥-secretasa 32,33 . Se ha indicado que el compuesto mejora el déficit de la función y la memoria cognitiva en modelos preclínicos de neuropatología de la EA 33 . Los estudios realizados en animales y ensayos en humanos han demostrado que NIC5-15 es seguro y además actúa como sensibilizador de las acciones de la insulina 32 .…”

The “Other” Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances inmyo‐Inositol Chemistry)

“…[103] Insulin prevents damage caused by the synaptic accumulation of amyloid β oligomers and this effect is enhanced by the presence of D-chiro-inositol. [104] D-chiro-Inositol-phosphoglycans move from the foetus to the placenta during pregnancy but diabetic women have lower concentrations of these compounds in the placenta. [105] Insulin resistance is a prominent feature of preeclampsia and D-chiro-inositol levels are increased in this condition and may contribute to insulin resistance.…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…Inositol stereoisomers, which are upregulated by metformin (Baillargeon et al, 2004), are anti-epileptogenic (Bazan and Musto, 2009), inhibit Aβ neurotoxicity and protect against the synaptic targeting by these oligomers (Pitt et al, 2013) in Alzheimer's disease.…”