Reports Weaken Death Receptor Link to Alzheimer's Disease

[3 January 2024 Editor's note: The paper that prompted the follow-up investigation covered below has been RETRACTED.]

Links between death receptor 6, a cell surface protein that triggers pruning of neuronal axons, and Alzheimer's disease are more tenuous than previously believed, according to new data. Five years ago, DR6 created excitement among Alzheimer’s researchers when Marc Tessier-Lavigne and colleagues at Genentech, San Francisco, reported that an N-terminal fragment of amyloid precursor protein (APP) activated the receptor, setting off an apoptotic cascade that targeted axons and neuronal cell bodies. The death pathway relied on β-secretase (BACE1) cleavage of APP, but was independent of amyloid-beta (Aβ), according to that work. Though the Genentech researchers had fleshed out these details using embryonic neurons, the finding raised the specter of an APP-dependent, and Aβ-independent, axonal degeneration pathway at work in the adult brain, as well (see Feb 2009 news story). Last year, Tessier-Lavigne, who has since moved to lead Rockefeller University, New York, and collaborators in Charles Gilbert’s laboratory there, showed that DR6 contributes to normal axon pruning in adult mice (see Sep 2013 news story), while a report by scientists at Biogen suggested that DR6 contributes to Aβ-driven pathology (see Hu et al., 2013). These spotlighted DR6 as a potential therapeutic target. 

The latter possibility now seems more remote. In back-to-back papers in the May 7 Journal of Neuroscience, Tessier-Lavigne and colleagues at Genentech including co-senior authors Robby Weimer and Kimberly Scearce-Levie publish follow-up data. They confirm that APP and DR6 do conspire to prune axons in the developing and adult brain, but they also report that this partnership has no bearing on amyloid pathology or cognitive decline. Knocking out DR6 in two different mouse models of AD did nothing to preserve learning and memory. 

"We were intrigued to see if this pathway underlies pathophysiology in mouse models of AD. It appears it does not," Tessier-Lavigne told Alzforum. The phenotypes in those mice, including increased plaque load, gliosis and behavioral deficits, are thought to be driven by Aβ, he said. By silencing DR6, the researchers could test the receptor’s involvement in mediating those actions of Aβ and of APP. "In short, the findings do not support a role for DR6 in the aspects of AD that are recapitulated in those models," said Tessier-Lavigne.  “It remains an open question whether DR6 contributes to axon degeneration observed in human AD, which is not modeled in those mice,” he added.   

Co-first authors Dara Kallop and William Meilandt crossed DR6 knockout mice with animals that express mutated human APP (APP41) and with PS2/APP double transgenic mice. Neither cross outperformed the parental AD strains in learning and memory tasks, indicating that DR6 does not contribute to these behavioral deficits.

In another twist, the researchers also absolve BACE1 of any involvement in APP/DR6-mediated axonal pruning. In their earlier work, they found that three different BACE inhibitors prevented APP-based axonal degeneration. Now, Kallop and colleagues report that while ablating APP or DR6 bumps up spine density in pyramidal neurons, knocking out BACE1 had no effect, suggesting its activity is not required to activate the APP/DR6 pathway. "This highlights the value of using genetic validation studies," said Weimer. Tessier-Lavigne told Alzforum that the researchers have traced their previous findings to off-target effects of the BACE inhibitors. 

The researchers did confirm that APP and DR6 work together in the same pathway to prune spines in both the mature central nervous system and, as reported in the second paper by co-first authors Olav Olsen and Kallop, in developing retinal ganglion cell axons in utero. Weimer told Alzforum that Genentech is no longer studying the DR6 pathway.  Tessier-Lavigne’s laboratory is. The Rockefeller scientists are now focusing on models involving pathological axonal degeneration.  “Only by studying such models will we be able to rule in or rule out a role for DR6 in pathological axon degeneration in disease,” he said.—Tom Fagan.

Comments

  1. Our unpublished look at this interaction showed by SPR and NMR that recombinant DR6 associates with APP via the disordered stalk domain, rather than the globular cys-rich domain.

    View all comments by Luke A. Miles

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References

News Citations

  1. Cellular Pruning Shears Reshape Connections in Adults

Research Models Citations

  1. PS2APP (PS2(N141I) x APPswe)

Paper Citations

  1. Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. Retraction Note: APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2024 Jan;625(7993):204. PubMed. Retracted Paper.
  2. Hu Y, Lee X, Shao Z, Apicco D, Huang G, Gong BJ, Pepinsky RB, Mi S. A DR6/p75(NTR) complex is responsible for β-amyloid-induced cortical neuron death. Cell Death Dis. 2013;4:e579. PubMed.

Other Citations

  1. Feb 2009 news story

Further Reading

Primary Papers

  1. Kallop DY, Meilandt WJ, Gogineni A, Easley-Neal C, Wu T, Jubb AM, Yaylaoglu M, Shamloo M, Tessier-Lavigne M, Scearce-Levie K, Weimer RM. A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer's disease-related pathophysiology in murine models. J Neurosci. 2014 May 7;34(19):6425-37. PubMed.
  2. Olsen O, Kallop DY, McLaughlin T, Huntwork-Rodriguez S, Wu Z, Duggan CD, Simon DJ, Lu Y, Easley-Neal C, Takeda K, Hass PE, Jaworski A, O'Leary DD, Weimer RM, Tessier-Lavigne M. Genetic analysis reveals that amyloid precursor protein and death receptor 6 function in the same pathway to control axonal pruning independent of β-secretase. J Neurosci. 2014 May 7;34(19):6438-47. PubMed.

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