Roy ER, Chiu G, Li S, Propson NE, Kanchi R, Wang B, Coarfa C, Zheng H, Cao W. Concerted type I interferon signaling in microglia and neural cells promotes memory impairment associated with amyloid β plaques. Immunity. 2022 May 10;55(5):879-894.e6. Epub 2022 Apr 19 PubMed.
Recommends
Please login to recommend the paper.
Comments
Columbia University Medical Center
The paper by Roy and colleagues explores an interesting, potentially new pathogenic pathway that links nucleic acid (NA) containing neuritic plaques to microglial type I interferon signaling and ultimately to complement mediated synapse loss in Alzheimer’s disease (AD). The seminal study by the late Trojanowski and colleagues reporting sequestration of RNA into neurofibrillary tangles and senile plaques in Alzheimer’s disease (Ginsberg et al., 1997) forms the conceptual basis of these investigations. Nucleic acids (NA), here complexed with amyloid fibrils, are potent inducers of an autocrine type I interferon (IFN-1) response in microglia and accordingly, in this study by Roy and colleagues, IFN-1 receptor (IFNAR) blockade rescued synapse elimination and cognitive deficits in the 5xFAD mouse model. Interesting in this report is the diversification of the effects of type I interferon signaling in neurons and microglia as it relates to synaptic pathology (pre- and post-synapse) as well as to amyloid plaques and hyperphosphorylated tau. Only ablating microglial IFNAR signaling resulted in reduced p-tau pathology, while the same intervention had no effect on amyloid pathology.
These findings are in line with our own observations in human Alzheimer’s disease (Olah et al., 2020), where the interferon response-dominated microglia phenotype (identified in an unbiased way through single-cell RNA sequencing) was found to associate with tau pathology, but not amyloid pathology in the ROS/MAP cohort. In the current study by Roy and colleagues, also intriguing are the findings regarding the overlap between microglia expressing interferon-stimulated genes (ISGs) and those expressing genes associated with the disease associated microglia (DAM) signature. In line with these results, we also saw some overlap between interferon response microglia cluster and the DAM-resembling microglia phenotype in human microglia isolated from AD brains, highlighting the importance of further studying the functional relevance of co-existence of these transcriptional programs in microglia in AD.
While the study offers an in-depth, mechanistic investigation of the “NA containing neuritic plaque—type I interferon response—cognitive impairment” axis, a couple of questions remain unanswered and warrant further exploration. It would be important to understand the exact mechanisms through which nucleic acids become entrapped in some, but not all, neurofibrillary tangles and senile plaques in AD, how their abundance is affected by AD risk factors and how their presence affects other pathological and clinical AD traits. Since the authors’ hypothesis is centered on NA sensing by microglia, it would be essential to identify which microglial receptor and pathway are responsible for the elicited phenotype. Additionally, further investigation of this pathogenic axis in humans, at different stages of AD disease progression, will reveal the utility of this pathway as a potential therapeutic target. And lastly, it would be critical to comprehend how the AD susceptibility genes/proteins interact with the many different components of this axis from NA sensing by microglia, through type I interferon response in neurons as well as in microglia to, ultimately, synapse elimination and cognitive decline.
References:
Ginsberg SD, Crino PB, Lee VM, Eberwine JH, Trojanowski JQ. Sequestration of RNA in Alzheimer's disease neurofibrillary tangles and senile plaques. Ann Neurol. 1997 Feb;41(2):200-9. PubMed.
Olah M, Menon V, Habib N, Taga MF, Ma Y, Yung CJ, Cimpean M, Khairallah A, Coronas-Samano G, Sankowski R, Grün D, Kroshilina AA, Dionne D, Sarkis RA, Cosgrove GR, Helgager J, Golden JA, Pennell PB, Prinz M, Vonsattel JP, Teich AF, Schneider JA, Bennett DA, Regev A, Elyaman W, Bradshaw EM, De Jager PL. Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease. Nat Commun. 2020 Nov 30;11(1):6129. PubMed.
University of California, Los Angeles
Both our prior work (Rexach, 2020) and that of others (Jin et al., 2021; Lall et al., 2021) point to microglial type 1 interferon as a driver of a distinct microglial type that promotes neuroinflammation in AD and other dementias.
This new work, including lineage tracing, puts microglial type 1 interferon signaling front and center as an important early event contributing to synapse pathology. This is particularly important because transcriptomically defined and heterogenous microglial states are reproducibly observed, but we don't know their distinct functions in disease.
This work brings us closer to a much-needed mechanistic understanding of pathological synaptic clearance and the role of type 1 interferon in disease. It’s also notable that Roy et al. found that microglial type 1 interferon can promote synaptic pathology independent of amyloid pathology, because this raises the possibility that type 1 interferon may promote a transition to amyloid-independent neuroinflammation. That now needs to be tested.
References:
Rexach JE, Polioudakis D, Yin A, Swarup V, Chang TS, Nguyen T, Sarkar A, Chen L, Huang J, Lin LC, Seeley W, Trojanowski JQ, Malhotra D, Geschwind DH. Tau Pathology Drives Dementia Risk-Associated Gene Networks toward Chronic Inflammatory States and Immunosuppression. Cell Rep. 2020 Nov 17;33(7):108398. PubMed.
Jin M, Xu R, Alam MM, Ma Z, Zhu S, Wang L, Martini AC, Bernabucci M, Xie P, Kwan K, Pang ZP, Head E, Liu Y, Hart RP, Jiang P. Type I Interferon Signaling Drives Microglial Dysfunction and Senescence in Human iPSC Models of Down Syndrome and Alzheimer’s Disease. bioRxiv. December 23, 2021 bioRxiv
Lall D, Lorenzini I, Mota TA, Bell S, Mahan TE, Ulrich JD, Davtyan H, Rexach JE, Muhammad AK, Shelest O, Landeros J, Vazquez M, Kim J, Ghaffari L, O'Rourke JG, Geschwind DH, Blurton-Jones M, Holtzman DM, Sattler R, Baloh RH. C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation. Neuron. 2021 Jul 21;109(14):2275-2291.e8. Epub 2021 Jun 15 PubMed.
Make a Comment
To make a comment you must login or register.