Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers

Abstract

Synapse deterioration underlying severe memory loss in early Alzheimer's disease (AD) is thought to be caused by soluble amyloid beta (Aβ) oligomers. Mechanistically, soluble Aβ oligomers, also referred to as Aβ-derived diffusible ligands (ADDLs), act as highly specific pathogenic ligands, binding to sites localized at particular synapses. This binding triggers oxidative stress, loss of synaptic spines, and ectopic redistribution of receptors critical to plasticity and memory. We report here the existence of a protective mechanism that naturally shields synapses against ADDL-induced deterioration. Synapse pathology was investigated in mature cultures of hippocampal neurons. Before spine loss, ADDLs caused major downregulation of plasma membrane insulin receptors (IRs), via a mechanism sensitive to calcium calmodulin-dependent kinase II (CaMKII) and casein kinase II (CK2) inhibition. Most significantly, this loss of surface IRs, and ADDL-induced oxidative stress and synaptic spine deterioration, could be completely prevented by insulin. At submaximal insulin doses, protection was potentiated by rosiglitazone, an insulin-sensitizing drug used to treat type 2 diabetes. The mechanism of insulin protection entailed a marked reduction in pathogenic ADDL binding. Surprisingly, insulin failed to block ADDL binding when IR tyrosine kinase activity was inhibited; in fact, a significant increase in binding was caused by IR inhibition. The protective role of insulin thus derives from IR signaling-dependent downregulation of ADDL binding sites rather than ligand competition. The finding that synapse vulnerability to ADDLs can be mitigated by insulin suggests that bolstering brain insulin signaling, which can decline with aging and diabetes, could have significant potential to slow or deter AD pathogenesis.

Molecular Mechanisms of Amyloid Oligomers Toxicity

“…Taken together, these data demonstrate that physiologically relevant levels of naturally secreted A␤ interfere with IR function and prevent the rapid activation of specific kinases required for long-term potentiation [46]. De Felice et al also suggest that ADDLs caused major downregulation of plasma membrane IRs, via a mechanism sensitive to CaMKII and casein kinase II inhibition [47].…”

Synthetic amyloid-β oligomers impair long-term memory independently of cellular prion protein

“…Several types of Aβ aggregate isolated from biological sources have been used in these studies. The mechanism through which Aβ oligomers act remains uncertain, but interactions have been reported with several receptors such as nicotinic, insulinic, and glutamatergic receptors, leading to detrimental effects on synaptic plasticity and spine formation (12)(13)(14)(15)(16). Recently, the cellular prion protein (PrP C ) has been proposed as another additional possible mediator of oligomer action.…”

Intranasal insulin treatment improves memory and learning in a rat amyloid-beta model of Alzheimer’s disease

“…According to the study by Wang et al (53), induction of diabetes in transgenic AD mice promotes the processing of Aβ precursor protein and results in increased Aβ generation, neuritic plaque formation, and spatial memory deficits. On the other hand, an accumulating body of evidence shows that Aβ binds to the insulin receptor and disrupts insulin signaling and long-term potentiation induction (12,15). Insulin also modulates glucose utilization in the hippocampus and other brain regions and facilitates memory at optimal levels in normal metabolism (31).…”