This week, two papers offer similar takes on how soluble Aβ interferes with insulin signaling, and might even avail itself of the insulin receptor to poison synapses. A third study explores the links between Aβ and the development of dendritic spines, and a fourth between Aβ and inflammation. Below is an update.

The newest finding, out yesterday online as a paper in press in the Journal of Biological Chemistry, implicates the insulin receptor and its signaling cascades in the shutdown of long-term potentiation induced by Aβ. In the study, Matthew Townsend (who since moved to Merck Research Labs in Boston), Tapan Mehta, and Dennis Selkoe at Harvard Medical School detected LTP inhibition in cultured primary hippocampal neurons after transient treatment with low concentrations of soluble Aβ oligomers. The scientists found that Aβ blocked activation of three kinases that are normally turned on during LTP induction, i.e., calmodulin dependent kinase II (CaMKII), Erk/MAPK, and Akt/PKB, while leaving alone PKA and PKC.

This pattern of selective inhibition matched that elicited by an insulin receptor kinase inhibitor (AG1024), which, like Aβ, inhibited LTP. This led the researchers to ask if Aβ acts through the insulin receptor to squelch LTP. In support of this idea, they show that soluble Aβ binds to the insulin receptor, inhibiting its autophosphorylation. In addition, excess insulin could partially reverse the inhibitory effects of Aβ on both kinase activation and LTP. This observation, they write, “supports the hypothesis that Aβ and insulin share common signal transduction pathways and that at least one aspect of Aβ-mediated synaptotoxicity may be through disruption of insulin signaling, either directly or indirectly.”

That is also the idea of a paper from William Klein’s lab at Northwestern University in Evanston, Illinois, published online August 24 in the FASEB Journal. Their data show that Aβ treatment results in a loss of insulin signaling, though perhaps through a different mechanism. First author Wei-Qin Zhao demonstrates that treating hippocampal neurons in culture with soluble Aβ oligomers (in their parlance, ADDLs), results in a loss of most dendritic insulin receptors. Redistribution of the receptors to the cell body greatly diminishes the cells’ response to insulin, and triggers an increase in phosphorylation of the Akt kinase at Ser473, a hallmark of insulin resistance in other diseases. As this group has shown for other ADDL-induced effects, the downregulation of insulin receptors depended on NMDA receptor activity (see ARF related news story). “These results identify novel factors that affect neuronal IR signaling and suggest that insulin resistance in AD brain is a response to ADDLs, which disrupt insulin signaling and may cause a brain-specific form of diabetes as part of an overall pathogenic impact on CNS synapses,” Zhao and colleagues write.

In the brain, insulin’s functions reach beyond glucose homeostasis to include synaptotrophic and neurotrophic effects. These new studies jibe with an emerging concept that neuronal insulin resistance is an important part of the pathology of AD (see ARF live discussion and ARF live discussion), and raise the possibility that Aβ oligomers may directly induce insulin resistance in neurons.

Whatever its early stages, one downstream result of Aβ’s assault on the brain is the massive synaptic loss that correlates with the cognitive decline of AD. A third paper, this one from Brad Hyman’s lab at the Massachusetts General Hospital in Boston shows that Aβ destabilizes dendritic spines, the neuronal protrusions that harbor synapses. To look at spine dynamics, first author Tara Spires-Jones and colleagues used in-vivo multiphoton microscopy to watch spines in the brains of living mice over an hour’s time. They found that even in aged control animals, most spines are stable, but a small proportion is in flux. These latter spines appear and disappear in equal numbers, keeping the total number steady. However, in Tg2576 APP-overproducing mice, the picture was different. In the neighborhood of amyloid plaques, disappearance of spines outstripped formation, leading to a net loss in spine density. Spines farther away from plaques were not disrupted. The authors propose that the plaques act as a source of diffusible soluble Aβ—which has been shown to change the composition of synaptic receptors (see ARF related news story) and the stability of synapses (see ARF related news story and ARF news story) in cultured neurons and in mouse brain in vivo. Their results indicate that the brain maintains its plasticity with age, but not in the presence of Aβ.

Finally, an enduring question concerning Aβ toxicity lies in the peptide’s propensity to induce neuroinflammation. It raises the question of the relative lethality of Aβ’s direct actions on neurons, versus its indirect assault via harmful inflammatory reactions. Recently, Yong Shen and colleagues at the Sun Health Research Institute, Sun City, Arizona, showed that the receptor for an important inflammatory mediator, tumor necrosis factor α (TNFα) was required for Aβ-induced neuronal death (Li et al., 2004). The receptor, the tumor necrosis factor type I receptor (TNFR1), is wired into the apoptotic machinery of cells, and functions as a death receptor.

Now, the same group shows that TNFR1 also plays a role in Aβ generation. In the August 27 Journal of Cell Biology, first authors Ping He and Zhenyu Zhong report that deleting the TNFR1 in App23 mice profoundly decreases Aβ generation and subsequent amyloid pathology. Compared with the parental line, the knockout mice had 80 percent fewer hippocampal amyloid plaques, less microglial activation, reduced neuronal loss, and better performance on memory tests. The effect appeared to stem from a reduction in β-secretase protein and activity, which was under the control of TNFα, the ligand for the TNFR1.

“These findings suggest that TNFR1 not only contributes to neurodegeneration but also that it is involved with APP processing and Aβ plaque formation,” the authors write. The work indicates that TNFα might be part of a positive feedback loop, where Aβ induces inflammation and TNF production, which then further increases Aβ production by boosting β-secretase. Blocking TNFR1 could present a new therapeutic target for AD, they conclude.—Pat McCaffrey.

References:
Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway JBC published September 13, 2007 as doi:10.1074/jbc.M610390200. Abstract

Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 2007 Aug 24; [Epub ahead of print] Abstract

Spires-Jones TL, Meyer-Luehmann M, Osetek JD, Jones PB, Stern EA, Bacskai BJ, Hyman BT. Impaired Spine Stability Underlies Plaque-Related Spine Loss in an Alzheimer's Disease Mouse Model. Am J Pathol. 2007 Aug 23; [Epub ahead of print] Abstract

He P, Zhong Z, Lindholm K, Berning L, Lee W, Lemere C, Staufenbiel M, Li R, Shen Y. Deletion of tumor necrosis factor death receptor inhibits amyloid {beta} generation and prevents learning and memory deficits in Alzheimer's mice. J Cell Biol. 2007 Aug 27;178(5):829-41. Abstract