Intrinsic antiviral immunity drives in Alzheimer disease

Stefano Pluchino, Cory Willis

J Clin Invest. 2020;130(4):1622-1624. https://doi.org/10.1172/JCI135906.

Commentary

β- aggregates found in brain plaques are viewed as triggers of cytotoxicity and neuroinflammation in Alzheimer disease (AD). However, the main β-amyloid (Aβ) species and what imbues the aggregates with such toxic potential are still not yet understood. In this issue of the JCI, Roy et al. show that Aβ complexed with nucleic acids triggers an antiviral type I interferon response in neuroglia, resulting in complement-mediated elimination in AD models. These findings identify a putative endogenous immune signaling axis that drives neurodegeneration in AD and has strong implications for the development of precise therapeutic strategies.

Find the latest version: https://jci.me/135906/pdf COMMENTARY The Journal of Clinical Investigation Intrinsic antiviral immunity drives neurodegeneration in Alzheimer disease

Stefano Pluchino and Cory Willis Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, United Kingdom.

I IFNs (i.e., Irf7, Cxcl10, Oas1) as well as AD-related proinflammatory factors (i.e., β-Amyloid aggregates found in brain plaques are viewed as triggers C3, Tnf, Il1β) (8), as shown in previous of cytotoxicity and neuroinflammation in Alzheimer disease (AD). studies (4). However, the main -amyloid (A ) species and what imbues the β β The in vitro exposure of mixed aggregates with such toxic potential are still not yet understood. In this cultures to NA+ generic amyloid induced issue of the JCI, Roy et al. show that Aβ complexed with nucleic acids a type I ISG signature and led to increased triggers an antiviral type I interferon response in neuroglia, resulting in IFN-β secretion in tissue-culture super- complement-mediated synapse elimination in AD models. These findings natants. This antiviral immune response identify a putative endogenous immune signaling axis that drives was markedly reduced when mixed glia neurodegeneration in AD and has strong implications for the development cultures were pretreated with a drug that of precise therapeutic strategies. depleted the culture of (lipo- some-encapsulated clodronate). These results suggest that NA+ amyloid triggers the activation of type I IFN signaling pre- dominantly in microglia. In vivo, the tran- A role for type I IFNs microgliosis, and astrogliosis, as well as scriptional analysis of the hippocampi The identification of a role for immune increased proinflammatory cytokine pro- from wild-type (WT) mice injected with cells in the progression of Alzheimer dis- duction (5). Soluble Aβ oligomers bind NA+ generic amyloid revealed an acti- ease (AD) has led to intense focus on the with negatively charged factors, such as vation profile comparable to that of the adaptive (1) and innate branches of the NAs, thus expediting the formation of experimental AD brains, as above. Indeed, immune system (2). Microglia are the main insoluble amyloid fibrils (6). Importantly, NA+ generic amyloid triggered antiviral innate immune cells present in the brain NA-containing amyloid fibrils potently responses onto microglial and and are equipped with the requisite classes activate dendritic cells and enable type I and in vivo, when injected into the brain of signalling receptors to sense and perpet- IFN production to stimulate systemic parenchyma (8). uate local (3). autoimmunity in mice (7). Further in vivo validation in the When intracellular innate immune sen- In this issue of the JCI, Roy et al. set 5XFAD mouse brain (9) revealed that the sors recognize viral or self-derived nucleic out to determine if NA-containing (NA+) vast majority of Aβ plaques contained acids (NAs), an activated antiviral state pro- amyloid fibrils were able to elicit sufficient NA inclusions, and that their frequency duces type I interferon (IFN) and induces production of type I IFN to drive neuroin- increased with age. Systematic analysis interferon-stimulated genes (ISGs). Type I flammation and neurodegeneration in the of these amyloid plaques demonstrated IFN signalling also mediates neuroinflam- AD brain (8). a substantial increase of reactive, phago- mation in AD, both in animal disease mod- The authors examined the transcrip- cytic microglia in close proximity to NA+ els and human subjects (4), which implies tional profile of a brain region crucial for plaques, whereas microglia near to NA– that this signalling pathway activates as an human memory and the main target in AD plaques remained nonphagocytic. NA+ integral response to disease progression. — the . They used a series of plaque-associated microglia exclusively In the AD brain, the accumulation animal models for AD (APPNL-G-F, 5XFAD, expressed the microglial neurodegener- of aggregated β-amyloid (Aβ) fibrils into APP;tTa, and APP-PS1) and showed ative phenotype (MGnD) marker Clec7a AD plaques occurs in concomitance with increased expression of gene markers for (10), whereas a complete absence of Cle- a chronic neuroinflammatory response microglia (Aif1) and astrocytes (Gfap). c7a expression was observed in microglia (5). This plaque-inflammatory response These changes were paralleled by upreg- associated with NA– plaques. These data includes the induction of ISGs, reactive ulation of genes that were induced by type suggest the coexistence of NA+ plaques and the induction of type I IFN signalling in a subset of (plaque-associated) MGnD Related Article: p. 1912 that constitute an integral element in the propagation of innate inflammatory Conflict of interest: SP is cofounder and chief scientific officer at Cambridge Innovation Technologies Consulting (CITC) Ltd. and iSTEM Therapeutics and cofounder and non–executive director at Asitia Therapeutics. responses in the AD brain. While con- Copyright: © 2020, American Society for Clinical Investigation. firming an upregulation of the astroglial Reference information: J Clin Invest. 2020;130(4):1622–1624. https://doi.org/10.1172/JCI135906. marker Gfap, this in vivo part of the study

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Figure 1. Model of type I IFN–mediated neuroinflammation and synapse loss in AD. NA+ amyloid induces a type I ISG signature leading to increased IFN-β secretion, predominantly in microglia. Type I IFNs act via IFN-α/β receptors (IFNARs) to induce type I IFNs and AD-related proinflammatory factors, such as C3 in astrocytes. Other microglia gene markers are also upregulated. Autocrine and paracrine signaling perpetuates cell activation and drives synapse loss and neurodegeneration.

failed to address the spatial organization 12-month old) APPNL-G-F mice injected tor induces the expression of complement of astrocytes in respect to Aβ plaques and with αIFNAR blocking antibody. Inter- . To this aim, the authors injected NA inclusions (8). estingly, αIFNAR blockade failed to alter stereotaxically rIFN-β into the hippocampi plaque load in both young 5XFAD and of WT mice and measured C3 at transcript Neuroinflammation and aged APPNL-G-F mice (8). Thus, type I IFNs and levels. Interestingly, rIFN-β synapse loss act via IFN-α/β receptors on microglia increased C3 expression in astrocytes only. Microglia, which mediate synaptic pruning and signal both autocrine and paracrine Conversely, the injection of NA+ generic during brain development (11, 12), are also pathways to perpetuate cell activation and amyloid into the hippocampi of WT mice responsible for synapse loss in neurode- drive synapse loss and neurodegeneration elicited a substantial induction of the generation (10). To identify a mechanism in the AD brain. expression of complement genes. The i.c.v. linking neuroinflammation with synapse injection of an αIFNAR attenuated the loss in AD, Roy and colleagues injected a The NA+ amyloid–type I IFN–C3 complement response, strongly suggest- potent type I IFN recombinant interferon-β signaling axis ing that type I IFNs signal through IFN-α/β (rIFN-β) into the brains of WT mice and Complement component 3 (C3) is recog- receptor onto astrocytes for complement evaluated the cellular and molecular effec- nized as a central mediator in the pruning activation in response to NA+ amyloid in tors that regulate several innate immune of weak tagged with complement AD. The authors confirmed these find- responses (13), including microglia acti- proteins by microglial cells expressing ings in the 5XFAD and APPNL-G-G mouse vation (14). Intracerebroventricular (i.c.v.) complement receptors during develop- AD models, where blocking αIFNAR with injection of rIFN-β induced the expression ment (11, 12). Complement proteins are an antibody reduced C3 protein and tran- of genes associated with the MGnD phe- also substantially upregulated during aging script expression, respectively. While NA+ notype and triggered a cellular response and neurodegeneration — even prior to any amyloid as well as the recombinant protein predominantly characterized by increased evidence of neuronal loss, which antic- stimulated type I IFN signaling in both in reactive, phagocytic microglia engulfing ipates a role for complement-mediated microglia and astrocytes, downstream synaptic puncta. Conversely, injecting mechanisms in neuronal dysfunction and complement activation occurred only in an αIFN-α/β receptor (αIFNAR) blocking loss (15). Furthermore, aging promotes sus- astrocytes (8). Therefore, the model pro- antibody into young (3-month-old) 5XFAD tained expression of type I IFN in the brain, posed here suggests that NA+ amyloid is mice suppressed type I IFN signalling in which induces an inflammatory microglia able to induce C3 production in astrocytes reactive microglia, reduced Clec7a expres- phenotype and leads to increased produc- but not in microglia (Figure 1). sion, and restored synaptic puncta density tion of complement factors (16). In experimental demyelination in mice, to control levels. Similar changes in micro- What remains to be established is C3 but not C1q has recently emerged as a gliosis were also identified in aged (10- to whether signaling through IFN-α/β recep- major driver of microglia engulfment and

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elimination of synapses (17). To address In summary, Roy et al. provide compel- 6. Di Domizio J, et al. Binding with nucleic acids whether C3 was indeed necessary for the ling evidence that neuroinflammation is a or glycosaminoglycans converts soluble protein oligomers to amyloid. J Biol Chem. type I IFN-triggered synapse elimination critical feature of AD pathobiology. While 2012;287(1):736–747. + in AD, the authors injected cerebral ventri- demonstrating that NA -containing amy- 7. Di Domizio J, et al. Nucleic acid-containing cles of C3–/– mice with rIFN-β and quanti- loid is a potent inducer of type I IFN signal- amyloid fibrils potently induce type I interferon fied microglia and synapses. Interestingly, ling in neuroglia, this study also addresses and stimulate systemic autoimmunity. Proc Natl while C3–/– microglia exhibited a reactive the key mechanisms of the induction and Acad Sci USA. 2012;109(36):14550–14555. 8. Roy ER, et al. Type I interferon response morphology, C3–/– brains were completely propagation of antiviral innate immune drives neuroinflammation and synapse protected from postsynaptic puncta loss responses in the brain, which in turn ampli- loss in Alzheimer disease. J Clin Invest. after rIFN-β compared with controls (8). fy complement-mediated synapse loss and 2020;130(4):1912–1930. Together, these results highlight a neurodegeneration (8). 9. Oakley H, et al. Intraneuronal beta-amyloid critical NA+ amyloid–type I IFN comple- These results not only expand our aggregates, neurodegeneration, and ment-mediated signaling axis that triggers understanding of the pathology in AD loss in transgenic mice with five familial Alzheimer’s disease mutations: potential fac- and perpetuates neuroglial reactivity and but also identify a putative endogenous tors in amyloid plaque formation. J Neurosci. drives synapse loss in AD. immune signaling axis driving neuroinflam- 2006;26(40):10129–10140. mation and neurodegeneration in AD, and 10. Krasemann S, et al. The TREM2-APOE pathway Conclusion may have strong implications for the devel- drives the transcriptional phenotype of dysfunc- The work by Roy et al. (8) proposes a role opment of precise therapeutic strategies. tional microglia in neurodegenerative diseases. Immunity. 2017;47(3):566–581.e9. + for NA amyloid as a potent inducer of type 11. Filipello F, et al. The microglial innate immune I IFN signalling and complement-mediat- Acknowledgments receptor TREM2 is required for synapse elimi- ed synapse elimination by microglia and The authors acknowledge current mem- nation and normal brain connectivity. Immunity. astrocytes in AD and potentially other bers of the Pluchino laboratory, who con- 2018;48(5):979–991.e8. neurodegenerative disorders. At the same tributed to (or inspired) this commentary. 12. Paolicelli RC, et al. Synaptic pruning by microg- lia is necessary for normal brain development. time, the study raises a number of ques- Science. 2011;333(6048):1456–1458. tions warranting further investigation. Address correspondence to: Stefano 13. Akira S, Uematsu S, Takeuchi O. Pathogen Further studies are required to estab- Pluchino, Clifford Allbutt Building, Cam- recognition and innate immunity. Cell. lish the specificity and the main source of bridge Biosciences Campus, Hills Road, 2006;124(4):783–801. cell-free NAs (i.e., DNA, RNA), and wheth- CB2 0HA Cambridge, United Kingdom. 14. Song WM, Colonna M. The identity and function of microglia in neurodegeneration. Nat Immu- er these might represent a potential disease Phone: 44.1223.331163; Email: spp24@ nol. 2018;19(10):1048–1058. biomarker to be detected and quantified in cam.ac.uk. 15. Hong S, et al. Complement and microglia medi- biological fluids (18). Additional mechanis- ate early synapse loss in Alzheimer mouse mod- tic work is also indispensable to identify 1. Gate D, et al. Clonally expanded CD8 T cells els. Science. 2016;352(6286):712–716. the key components of this antiviral type patrol the in Alzheimer’s dis- 16. Deczkowska A, et al. Mef2C restrains microglial inflammatory response and is lost in brain age- I IFN–mediated neuroglia reaction, and ease. Nature. 2020;577(7790):399–404. 2. Taylor JM, Moore Z, Minter MR, Crack PJ. ing in an IFN-I-dependent manner. Nat Com- to address the relative contribution of the Type-I interferon pathway in neuroinflam- mun. 2017;8(1):717. autocrine versus paracrine signaling path- mation and neurodegeneration: focus on 17. Werneburg S, et al. Targeted complement inhi- ways — both mediated by soluble factors Alzheimer’s disease. J Neural Transm (Vienna). bition at synapses prevents microglial synaptic and associated with extracellular mem- 2018;125(5):797–807. engulfment and synapse loss in demyelinating brane vesicles (19) — in the perpetuation of 3. Olson JK, Miller SD. Microglia initiate central disease. Immunity. 2020;52(1):167–182.e7. nervous system innate and adaptive immune 18. Pös O, Biró O, Szemes T, Nagy B. Circulating neuroinflammation in AD. Nonetheless, it responses through multiple TLRs. J Immunol. cell-free nucleic acids: characteristics and appli- will also be important to determine if this 2004;173(6):3916–3924. cations. Eur J Hum Genet. 2018;26(7):937–945.l. endogenous type I IFN–driven response 4. Taylor JM, Minter MR, Newman AG, Zhang M, 19. Cossetti C, et al. Extracellular vesicles from to NA+ amyloid, and its consequences on Adlard PA, Crack PJ. Type-1 interferon signal- neural stem cells transfer IFN-γ via Ifngr1 to excessive synapse elimination and neu- ing mediates neuro-inflammatory events in activate Stat1 signaling in target cells. Mol Cell. models of Alzheimer’s disease. Neurobiol Aging. 2014;56(2):193–204. rodegeneration, plays any role in non-AD 2014;35(5):1012–1023. 20. Labzin LI, Heneka MT, Latz E. Innate immu- chronic neurological conditions associated 5. Scheltens P, et al. Alzheimer’s disease. Lancet. nity and neurodegeneration. Annu Rev Med. with increased type I IFN serology (20). 2016;388(10043):505–517. 2018;69:437–449.

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