Reifschneider A, Robinson S, van Lengerich B, Gnörich J, Logan T, Heindl S, Vogt MA, Weidinger E, Riedl L, Wind K, Zatcepin A, Pesämaa I, Haberl S, Nuscher B, Kleinberger G, Klimmt J, Götzl JK, Liesz A, Bürger K, Brendel M, Levin J, Diehl-Schmid J, Suh J, Di Paolo G, Lewcock JW, Monroe KM, Paquet D, Capell A, Haass C. Loss of TREM2 rescues hyperactivation of microglia, but not lysosomal deficits and neurotoxicity in models of progranulin deficiency. EMBO J. 2022 Feb 15;41(4):e109108. Epub 2022 Jan 12 PubMed.

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  1. This interesting study shows that interfering with microglia seems more complicated than anticipated. A better understanding of the neuroprotective versus neurotoxic properties of microglia is instrumental for designing therapeutic strategies. Microglial dysfunction seems context-, disease-, and disease-stage dependent.

    Simply reducing the activation of microglia may be too simplistic as an approach, at least for some diseases. It would be of interest to better understand the negative consequences of TREM2 inhibition and TREM2 deletion on lysosomal dysfunction and turnover and accumulation of insoluble TDP-43. In addition, it may be of interest to investigate the consequences of agonistic TREM2 antibodies, as well.

    View all comments by Philip Van Damme

  2. I have written extensively about the challenge of harnessing the immune system for therapeutic benefit in neurodegenerative diseases (see for example (Golde et al., 2018).

    The Goldilock's principle no doubt applies here, as well. Depending on the readout, it's hard to get the just the right temperature (which, in this case, is the immune activation state). Further, what the readout is in preclinical models that is needed to possibly predict clinical impact is debatable.

    This elegant paper shows another example of the delicate balance between beneficial and harmful effects of immune activation in the CNS. We have numerous examples where manipulating immune activation states beneficially impacts one pathology, accelerates another and, in some cases, can cause outright neurodegeneration.

    There is immense interest in therapeutically manipulating TREM2 and other immune targets in the brain, especially in AD. Indeed, we are already there, testing a few such therapies in humans. In the past, such studies, e.g. of NSAIDs, have probably done as much harm as good, and I would argue that our understanding of potential beneficial and untoward impacts is so nascent that we need a much more cautious data-driven approach.

    I would also argue that we need to be be thinking about the peripheral impacts of these manipulations as well. In this case, do TREM2 antagonist antibodies impact osteoclast function and bone mineralization (or other aspects of peripheral immune function)?

    I think a Pollyanna-ish view of these emerging therapeutic strategies will likely result in a suboptimal or even untoward outcome. All involved in these types of studies need to engage a bit more to discuss what kind of preclinical data is needed to move a therapeutic strategy forward toward humans. For example, should we insist that if AD is the disease of interest, we test in both amyloid and tau models, and what do we do if a beneficial effect is seen on one pathology and a harmful effect on the other?

    References:

    Golde TE. Harnessing Immunoproteostasis to Treat Neurodegenerative Disorders. Neuron. 2019 Mar 20;101(6):1003-1015. PubMed.

    View all comments by Todd E. Golde

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