The AppNL-G-F mouse model of Alzheimer’s disease is refractory to regulatory T cell treatment

Yshii, Lidia; Mascali, Loriana; Kouser, Lubna; Lemaître, Pierre; Marino, Marika; Dooley, James; Burton, Oliver T.; Haughton, Jeason; Callaerts-Végh, Zsuzsanna; Strooper, Bart De; Holt, Matthew; Pasciuto, Emanuela; Liston, Adrian

doi:10.1101/2022.03.11.483903

Cited by 4 publications

(5 citation statements)

References 35 publications

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“…APP NL-G-F mice have been developed to recapitulate expression profiles of risk factor genes, key aspects of neuroinflammation, and Aβ plaque deposition, similar to that in AD patients [49]. With glial activation starting at 2 months of age, it has been suggested that intense neuroinflammation happens between 3-6 months of age in APP NL-G-F with a peak at around 4 months of age [50]. There is corresponding synaptic dysfunction without neuronal death, which is consistent with our observation in the initiation of a low level of necroptotic process.…”

Section: Discussionmentioning

confidence: 99%

“…Having observed the effects of TNF in autolysosomal dysfunction and necroptosis in SH-SY5Y cells, we sought to investigate whether similar pathogenic mechanisms are present in the APP NL-G-F mouse model of AD and whether AcNPs can provide therapeutic effect in vivo. Glial activation and neuroinflammation are known to be present in the APP NL-G-F mice starting at 2-month-old [49], which has been shown to peak at 4-month-old with a sustained but lower level of inflammation at a later age [50]. We selected an early age of WT and APP NL-G-F mice at 3-month-old with glial activation (Fig.…”

Section: Stereotaxic Injection Of Acnps Restore Autolysosomal Functio...mentioning

confidence: 99%

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Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

Lo,

Zeng,

Loi

et al. 2023

Preprint

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Background: Tumor necrosis factor (TNF) receptor 1 (TNFR1) signaling mediates neuronal necroptosis in Alzheimer's disease (AD). Interaction of TNFR1 signaling axis with autolysosomal pathway and the accumulation of necrosome molecules in impaired lysosomes have been shown to lead to necroptotic neuronal death. This has been attributed to the terminal failure of the autophagic process, primarily due to lysosomal degradation dysfunction. Being the final and determining step of the autolysosomal pathway, lysosomes with sufficient acidification as maintained by functional vacuolar (H+)-ATPase (V-ATPase) are required to achieve complete autophagic degradation of toxic cellular components. Here, we aim to investigate the role of defective lysosomal acidification in mediating TNFR1 induced neuronal necroptosis in AD. Methods: Neuropathological analysis of human post-mortem AD brains was performed to examine the correlation between TNFR1 induced neuronal necroptosis and autolysosomal dysfunction. Specifically, we probed for the level of V-ATPase subunits in AD brains to determine the extent of lysosomal acidification and function. Cell-based assays were conducted to understand the effect of TNFR1 activation in driving lysosomal acidification defect, autophagic impairment, mitochondrial dysfunction, and neuronal death in SH-SY5Y neuroblastoma cells. Furthermore, we applied lysosome-acidifying nanoparticles (AcNPs) to determine whether restoration of lysosomal acidification can rescue neuronal necroptosis in both TNF-treated SH-SY5Y cells and APP-NL-G-F knock-in mouse model of AD. Results: We revealed that TNFR1 activated neuronal necroptosis correlates with autolysosomal dysfunction as characterized by downregulation of V-ATPase subunits and accumulation of autophagy receptor p62 in human AD brains. In cell culture, we showed for the first time that lysosomal acidification is only impaired in cells treated with TNF and not with other cytokines, contributing to inhibition of autophagic degradation in SH-SY5Y cells. We also illustrated that there is defective mitochondrial turnover, together with reduced mitochondrial functions and elevated reactive oxygen species, leading to neuronal death in SH-SY5Y cells. Importantly, we demonstrated that AcNPs restore lysosomal acidification, autophagic activity, and mitochondrial function, as well as rescue neuronal necroptosis in both TNF-treated SH-SY5Y cells and APP-NL-G-F mice. Conclusions: Defective lysosomal acidification plays a key role in TNFR1 mediated neuronal necroptosis. This opens avenues for new therapeutic strategies to target lysosomal acidification dysfunction in AD.

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Section: Discussionmentioning

confidence: 99%

Section: Stereotaxic Injection Of Acnps Restore Autolysosomal Functio...mentioning

confidence: 99%

Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

Lo,

Zeng,

Loi

et al. 2023

Preprint

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“…A possibility remains that these identified genes may affect the ageing of the brain and progression of AD by interaction of CNS-resident microglia with other immune cells associated with the blood-brain barrier or throughout the body. T cell changes in the brain that may contribute to ageing and AD have been discussed above [64][65][66][67] . Putative ageingassociated genes include CASP8, FES, ZKSCAN5, JAM3, STAT3 and USP38, which are expressed by multiple immune cells.…”

Section: General Immune System Changes May Govern Whole Organism Ageingmentioning

confidence: 99%

“…In contrast, agedependent genes unique to humans were associated with leukocyte activation, cytokine production and T cell activation. Recent studies have indicated that T cells expand in the brain during AD and ageing, and may contribute to disease progression [64][65][66][67][68] . Thus, microglial genes especially age-regulated in humans may contribute to ageing and AD, in part by recruitment and/or activation of other immune cells, including T cells.…”

Section: Differences Between Human and Mice Age-related Microglial Re...mentioning

confidence: 99%

Genetic variation associated with human longevity and Alzheimer's disease risk act through microglia and oligodendrocyte cross-talk

Graham

Bellou

Harwood

et al. 2023

Preprint

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Ageing is the greatest global healthcare challenge, as it underlies age-related functional decline and is the primary risk factor for a range of common diseases, including neurodegenerative conditions such as Alzheimer's disease (AD). However, the molecular mechanisms defining chronological age versus biological age, and how these underlie AD pathogenesis, are not well understood. The objective of this study was to integrate common human genetic variation associated with human lifespan or AD from Genome-Wide Association Studies (GWAS) with co-expression networks altered with age in the central nervous system, to gain insights into the biological processes which connect ageing with AD and lifespan. Initially, we identified common genetic variation in the human population associated with lifespan and AD by performing a gene-based association study using GWAS data. We also identified preserved co-expression networks associated with age in the brains of C57BL/6J mice from bulk and single-cell RNA-sequencing (RNA-seq) data, and in the brains of humans from bulk RNA-seq data. We then intersected the human gene-level common variation with these co-expression networks, representing the different cell types and processes of the brain. We found that genetic variation associated with AD was enriched in both microglial and oligodendrocytic bulk RNA-seq gene networks, which show increased expression with ageing in the human hippocampus, in contrast to synaptic networks which decreased with age. Further, longevity-associated genetic variation was modestly enriched in a single-cell gene network expressed by homeostatic microglia. Finally, we performed a transcriptome-wide association study (TWAS), to identify and confirm new risk genes associated with ageing that show variant-dependent changes in gene expression. In addition to validating known ageing-related genes such as APOE and FOXO3, we found that Caspase 8 (CASP8) and APOC1 show genetic variation associated with longevity. We observed that variants contributing to ageing and AD balance different aspects of microglial function suggesting that ageing-related processes affect multiple cell types in the brain. Specifically, changes in homeostatic microglia are associated with lifespan, and allele-dependent expression changes in age-related genes control microglial activation and myelination influencing the risk of developing AD. We identified putative molecular drivers of these genetic networks, as well as module genes whose expression in relevant human tissues are significantly associated with AD-risk or longevity, and may drive "inflammageing." Our study also shows allele-dependent expression changes with ageing for genes classically involved in neurodegeneration, including MAPT and HTT, and demonstrates that PSEN1 is a prominent member/hub of an age-dependent expression network. In conclusion, this work provides new insights into cellular processes associated with ageing in the brain, and how these may contribute to the resilience of the brain against ageing or AD-risk. Our findings have important implications for developing markers indicating the physiological age and pre-pathological state of the brain, and provide new targets for therapeutic intervention.

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“…The results have, however, been inconsistent across models and with different modalities of treatment. For example, in AD, direct cell therapy with Tregs (Baek et al , 2016 ; Faridar et al , 2022 ; Yang et al , 2022 ) has given beneficial effects, although other studies have shown the reverse (Baruch et al , 2015 ; Yang et al , 2020 ), while treatment with IL2 has given conflicting results, depending on the AD model, ranging from protective (Baek et al , 2016 ; Alves et al , 2017 ) to minor (Dansokho et al , 2016 ) or no effect (preprint: Yshii et al , 2022a ). In PD models, a number of different Treg‐based treatments have been beneficial, including direct cell transfer (Reynolds et al , 2007 ; Huang et al , 2020 ; Markovic et al , 2022 ), using bee venom phospholipase A2 to induce Treg formation, superagonist anti‐CD28 antibodies to expand them (Badr et al , 2022 ) or vasoactive intestinal peptide receptor‐2 (VIPR2) peptide agonist to enhance activity (Mosley et al , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

et al. 2023

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Cognitive decline is a common pathological outcome during aging, with an ill-defined cellular or molecular basis. Among the cellular changes observed with age are alterations to neuronal plasticity, changes in the glial compartment and the decline of the neurogenic niche.In the recent years, the concept of inflammaging, defined as a low-grade inflammation increasing with age, has emerged as a nexus for age-related diseases. This increase of basal inflammation is also observed in the central nervous system. While not classically considered a neurological cell type, infiltrating T cells increase in the brain with age, and may be responsible for amplification of inflammatory cascades and disruptions to the neurogenic niche. Recently, a small resident population of regulatory T cells has been identified in the brain, and the capacity of IL2-mediated expansion of this population to counter neuroinflammatory disease has been demonstrated. Here we test a brain-specific IL2 delivery system for the prevention of neurological decline in aging mice. We identify the molecular hallmarks of aging in the brain glial compartments, and identify partial restoration of this signature through IL2 treatment. At a behavioral level, brain IL2 delivery prevented the ageinduced defect in spatial learning, without improving the general decline in motor skill or arousal. These results identify immune modulation as a potential path to preserving cognitive function for healthy ageing.

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The App^NL-G-F mouse model of Alzheimer’s disease is refractory to regulatory T cell treatment

Cited by 4 publications

References 35 publications

Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

Defective lysosomal acidification contributes to TNFR1 mediated neuronal necroptosis in Alzheimer’s disease

Genetic variation associated with human longevity and Alzheimer's disease risk act through microglia and oligodendrocyte cross-talk

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

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