Koper MJ, Van Schoor E, Ospitalieri S, Vandenberghe R, Vandenbulcke M, von Arnim CA, Tousseyn T, Balusu S, De Strooper B, Thal DR. Necrosome complex detected in granulovacuolar degeneration is associated with neuronal loss in Alzheimer's disease. Acta Neuropathol. 2020 Mar;139(3):463-484. Epub 2019 Dec 4 PubMed.

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  1. I think the demonstration of necrosomes’ positive granulovacuolar degeneration (GVDn+) in AD brains is interesting and new, and opens up new lines of research and potentially new therapeutic targets.

    However, I think the mechanistic relationship between neurofibrillary tangles (NFTs) and GVDn+ should be investigated further. There is an inherent fundamental limitation with positive correlations based on snapshot data, such as neuropathology. I agree that a positive correlation does suggest that a relationship exists. But as we first showed many years ago for a different disease, it is very difficult to know the true nature of that relationship from snapshots.

    It is conventional to interpret positive correlations as pathogenic responses/mechanisms because it is intuitive. But coping mechanisms can actually be positively correlated, too, if the cellular abnormality is a response to stress and part of some mechanism to stave off cell death. The only way we could distinguish positive correlations due to pathogenic mechanisms from coping responses was to invent a method to follow single cells longitudinally and then quantify the predictive relationship of cytopathology for neurodegeneration using the same tools that are used for clinical trials.

    Mind you, this is no criticism of the paper. As I mentioned, it’s an inherent limitation in all data produced using snapshot approaches versus longitudinal single-cell analyses. I dare say that it was likely the positive correlation between amyloid plaques and AD and the interpretation of that relationship that led to so much investment by the pharmaceutical industry into therapies that target amyloid. The results of those clinical trials would suggest that we need to at least be aware of the inherent limitation of inferring biological mechanisms from snapshots and suggest a measure of caution.

    It would be exciting to follow up a study like this with longitudinal single-cell analysis of NFT formation and its relationship to GVDn+ to bring additional clarity.

    View all comments by Steven Finkbeiner

  2. This was a very nice study of AD patients and control brain samples, showing the presence of pRIPK1, pRIPK3, and pMLKL in granulovacuolar degeneration (GVD) of neuronal cells. The analyses are solid and convincing. Although differences exist with regard to the co-localization of RIPK1 and RIPK3, as well as the localization of pMLKL, compared with a previous study the findings add further evidence that necroptosis is involved in neuronal degeneration in AD (Caccamo et al., 2017). 

    Although activated necrosomes were demonstrated to be present in GVD of neuronal cells, the role of necroptosis in neurodegeneration still needs to be validated. The ongoing clinical studies of highly selective RIPK1 inhibitors in AD may provide clinical evidence to support the pathological roles of necroptosis.

    References:

    Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, Readhead B, Dudley JT, Spangenberg EE, Green KN, Belfiore R, Winslow W, Oddo S. Necroptosis activation in Alzheimer's disease. Nat Neurosci. 2017 Sep;20(9):1236-1246. Epub 2017 Jul 24 PubMed.

    View all comments by Shijun Zhang

  3. This study raises three major questions: Do neurons undergo a delayed slow necroptosis in AD? If so, how do microglia respond? And do microglia undergo necroptosis in AD?

    The authors demonstrate co-localization of activated necrosome components within cytoplasmic vacuolar lesions (GVD lesions) in neurons, and hypothesize that the sequestration of these components could be protective because it would prevent their pore-forming activity at the plasma membrane. Although the density of GVD neurons testing positive for phosphorylated MLKL, a necrosome marker, is higher in areas of increased neuronal loss in AD brains, it’s not clear whether these neurons will eventually die, or if they are detected because they’ve protected themselves from necroptosis. It would be interesting to follow up by tracking neuronal behavior over time in experimental models that manifest GVD lesions.

    These findings also raise the interesting question as to how microglia respond to necroptosing neurons, and whether this differs if the necroptosis is delayed or protracted. Interestingly, in this study, microglia appear to associate with necroptosing neurons in tissue from people with preclinical AD. This would position microglia to respond to the DAMPs, aka damage-associated molecular patterns, which are robustly released through necroptosis, which could in turn modify microglial behavior. Necroptosis has been associated with both pro-inflammatory and anti-inflammatory responses in different contexts, yet how microglia respond to necroptosis in AD, and how this impacts pathology, remain to be investigated.

    As for necroptosis in microglia, Koper et al. did not detect activated necroptosis component expression in microglia in AD, however, a previous study found that almost 30 percent of p-MLKL+ cells in AD brain were positive for the microglial marker Iba1+ (Caccamo et al., 2017). This raises the question as to why there is such a discrepancy between the studies, and how prevalent microglia necroptosis is in AD. If microglia do indeed undergo necroptosis in AD, does this lead to repopulation of the cells? Microglia repopulation following their death (experimental or occurring following injury) is robust, and can change their activation profile, which influences neural cells in their vicinity. For instance, we’ve shown that microglia undergo necroptosis following acute demyelination of white matter, followed by repopulation associated with pro-regenerative function (Lloyd et al., 2019). However, experimental microglial depletion can lead to repopulation of a neurodegenerative phenotype in select areas of gray matter (Rubino et al., 2018). Whether microglial necroptosis and repopulation are important regulators of AD pathology is unknown, but would be of paramount interest to the AD community.

    References:

    Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, Readhead B, Dudley JT, Spangenberg EE, Green KN, Belfiore R, Winslow W, Oddo S. Necroptosis activation in Alzheimer's disease. Nat Neurosci. 2017 Sep;20(9):1236-1246. Epub 2017 Jul 24 PubMed.

    Lloyd AF, Davies CL, Holloway RK, Labrak Y, Ireland G, Carradori D, Dillenburg A, Borger E, Soong D, Richardson JC, Kuhlmann T, Williams A, Pollard JW, des Rieux A, Priller J, Miron VE. Central nervous system regeneration is driven by microglia necroptosis and repopulation. Nat Neurosci. 2019 Jul;22(7):1046-1052. Epub 2019 Jun 10 PubMed.

    Rubino SJ, Mayo L, Wimmer I, Siedler V, Brunner F, Hametner S, Madi A, Lanser A, Moreira T, Donnelly D, Cox L, Rezende RM, Butovsky O, Lassmann H, Weiner HL. Acute microglia ablation induces neurodegeneration in the somatosensory system. Nat Commun. 2018 Nov 1;9(1):4578. PubMed.

    View all comments by Veronique Miron

  4. This extensive and well-performed study by Koper et al. shows an interesting novel feature of GVBs, as their core is immunopositive for necrosomes. As the authors and commentators indicate, caution is warranted with mechanistic interpretation based on observations in neuropathological tissue, which are indeed “snapshots.”

    Mechanistic insight may be facilitated by the neuronal GVB cell model recently developed in my lab (Wiersma et al., 2019). Using this model we could go beyond correlations and clearly establish causality between intracellular tau aggregation and GVB formation.

    In addition, this allowed a better characterization of GVBs, and we demonstrated that (contrary to what is stated in the commentary above) GVBs are single-membrane, proteolytically active lysosomes. The presence of necrosomes in GVBs further stresses the importance to investigate whether GVBs are a protective or degenerative response in tau pathogenesis (Wiersma and Scheper, 2019).

    References:

    Wiersma VI, van Ziel AM, Vazquez-Sanchez S, Nölle A, Berenjeno-Correa E, Bonaterra-Pastra A, Clavaguera F, Tolnay M, Musters RJ, van Weering JR, Verhage M, Hoozemans JJ, Scheper W. Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology. Acta Neuropathol. 2019 Dec;138(6):943-970. Epub 2019 Aug 27 PubMed.

    Wiersma VI, Scheper W. Granulovacuolar degeneration bodies: red alert for neurons with MAPT/tau pathology. Autophagy. 2020 Jan;16(1):173-175. Epub 2019 Oct 23 PubMed.

    View all comments by Wiep Scheper

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