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Ofengeim D, Mazzitelli S, Ito Y, DeWitt JP, Mifflin L, Zou C, Das S, Adiconis X, Chen H, Zhu H, Kelliher MA, Levin JZ, Yuan J. RIPK1 mediates a disease-associated microglial response in Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8788-E8797. Epub 2017 Sep 13 PubMed.
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University of California, San Francisco
RIPK is an interesting molecule. It is involved in multiple biological responses that can be broadly divided into three major pathways. Surprisingly, only one of those three depends on its kinase activity. One of the new ideas in protein biology is that kinases can serve multiple functions, and only some may depend on their kinase activity.
We became interested in RIPK because it was a hit in a screen we did to discover genes that modify progranulin expression levels (Mason et al., 2017). Progranulin deficiency leads to neurodegenerative disease. Haploinsufficiency causes frontotemporal dementia and rare patients with no progranulin develop neuronal ceroid lipofucinosis. There are genetic variants of progranulin that some believe may affect the risk of developing AD, and there are preclinical results suggesting that the level of progranulin in mice affects amyloid formation in mutant APP mouse models. Consistent with the main findings of this study, the conclusion of that work was that progranulin levels were working primarily by regulating microglial function to affect amyloid clearance.
It’s interesting to consider the possibility that the effects described in this paper of RIPK1 inhibition on amyloid might be mediated by microglia. However, one wrinkle is that we found that the kinase activity of RIPK1 was not required for its ability to regulate progranulin levels. We did not find any effect of the necrostatin RIPK1 inhibitor on progranulin levels. So, at the moment, it’s unclear whether and how the effects of RIPK1 on progranulin and progranulin on amyloid might be related to the observations described here.
That said, there is potentially another interesting connection. The authors here believe that the effects might be mediated through an effect of Cst7 and detrimental effects on the lysosome. That is interesting because we and others have found that progranulin haploinsufficiency impairs lysosomal function, which can cause hyper activation of microglia and poor neuronal proteostasis. That could contribute to neurodegeneration by making neurons more vulnerable and by enhancing the toxicity of the environment.
References:
Mason AR, Elia LP, Finkbeiner S. The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels. J Biol Chem. 2017 Feb 24;292(8):3262-3272. Epub 2017 Jan 9 PubMed.
View all comments by Steven FinkbeinerUniversitat Autònoma de Barcelona
The finding that genetic and pharmacological inhibition of RIPK1, a kinase overexpressed in plaque-associated microglia recently defined as disease-associated microglia (DAM), has therapeutic benefits in APP/PS1 mice adds little to the debate as to whether DAM are a dead-end product, as I believe, or a protective reaction optimized by evolution in the context of “neuroinflammation,” as the creators of the notion of DAM support. This study strictly shows that RIPK1 inhibition eliminates DAM, suggesting that RIPK1 participates in their generation. But this is hardly a breakthrough: when inhibited in mouse models, numerous microglia pathways result in the disappearance of DAM, along with reduction of plaque burden and memory deficits. Translation of these therapies to the clinic is still work in progress.
What, then, might be unique about RIPK1?
First, RIPK1 could be a superior target because it appears to be a signaling hub. An asset of the study is the network analysis of adult isolated microglia from mice with genetic inactivation of RIPK1. The analysis has led to the identification of several transcription factors as downstream targets of the kinase. This suggests that RIPK1 is a pleiotropic kinase controlling microglia phenotype through multiple transcriptional programs. It follows that therapeutical inhibition of RIPK1 may globally hamper maladaptive stress reactions of microglia.
Second, the in-depth characterization of RIP1K-dependent pathways may provide insight into which microglia functions are altered in AD. Based upon a series of in vitro studies, the authors favor the notion that aberrant RIP1K activation impairs lysosomal function in microglia by overexpression of the protease inhibitor cystatin F, thereby reducing Aβ clearance and contributing to plaque formation. However, their unbiased network analysis in RIPK1-deficient microglia shows dysregulation of up to 20 pathways different from “lysosomal function.” It would be interesting to clarify the roles of these pathways in healthy and diseased microglia, and their relationship with pathways regulated by microglia genes identified as genetic risk factors in AD by GWAS.
Even if the authors are right about RIP1K causing impairment of Aβ clearance in DAM, other possibilities cannot be excluded. For example, aberrant RIPK1 activation in microglia might impair their crosstalk with neurons and astrocytes, which may lead, in turn, to increased levels of soluble Aβ due to enhanced production by neurons (Cirrito et al., 2005) and reduced clearance by astrocytes (Iliff et al., 2012). All in all, we do not know how pharmacologically or genetically restored microglia reverse pathology. Any conclusion, like the very reasonable one that microglia take up Aβ, is based upon indirect evidence. When it comes to microglia, the early stages of AD are a black box and we need to refine our experimental tools and questions to cast a light on it.
View all comments by Elena GaleaUniversité Laval
These findings are particularly interesting, as they provide novel insights into the microglial phenotypic changes implicated in AD pathology.
Whether Cst7 can be considered a biomarker of the DAM phenotype should be investigated further. Cst7 has been shown to be upregulated by the DAM (Keren-Shaul et al., 2017), but it still remains undetermined whether all DAM do express Cystatin F, and whether Cst7 is exclusive to this microglial subpopulation.
Determining whether inhibiting the RIPK1 pathway could be used to prevent the DAM phenotype, and perhaps to generate animal models devoid of DAM, is a promising research area to pursue. It will be important in future investigations to assess the impact of DAM microglia on synaptic loss and cognition across various disease contexts.
References:
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, David E, Baruch K, Lara-Astaiso D, Toth B, Itzkovitz S, Colonna M, Schwartz M, Amit I. A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. Cell. 2017 Jun 15;169(7):1276-1290.e17. Epub 2017 Jun 8 PubMed.
View all comments by Marie-Eve TremblayMake a Comment
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