The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index; none of the 45 sources its claims cite is checked for support yet.
Role of USP16 in Aβ1–42-Induced Alzheimer's Disease: Targeting IFI16 to Alleviate the Inflammatory Response
Open accessAbstract
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) accumulation, neuroinflammation, and neuronal loss. Interferon gamma-inducible protein 16 (IFI16) regulates inflammatory processes in AD, while ubiquitin-specific peptidase 16 (USP16) has been shown to ameliorate memory deficits in AD models. This study aimed to elucidate the interplay between USP16 and IFI16 in AD pathogenesis. Methods: Differentially expressed genes associated with AD were identified using dataset GSE129296. Glial cells were exposed to β-amyloid peptide (Aβ)1–42 to establish an in vitro AD model, followed by indirect co-culture with neuronal cells. Neuronal viability and apoptosis were evaluated using the Cell Counting Kit-8 assay and flow cytometry, respectively. Levels of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in model glial cells were quantified by Enzyme-linked immunosorbent assay (ELISA). A potential deubiquitylating enzyme of IFI16 was predicted using Ubibrowser and confirmed by co-immunoprecipitation, while the ubiquitination levels of IFI16 were assessed. The expression of USP16/IFI16 and toll-like receptor 4 (TLR4)/NLR family pyrin domain containing 3 (NLRP3) was determined by reverse transcription-quantitative PCR (RT-PCR) and western blotting. Results: IFI16 was markedly upregulated in AD. Silencing of IFI16 attenuated Aβ1–42-induced proinflammatory responses in glial cells, reduced neuronal apoptosis, and enhanced neuronal viability, accompanied by decreased inflammatory cytokine levels and downregulation of TLR4/NLRP3 expression. USP16, identified as the deubiquitylating enzyme of IFI16, was significantly elevated in Aβ1–42-stimulated glial cells, and its silencing reduced IFI16 expression. Furthermore, IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation. Conclusion: USP16 depletion alleviates inflammation and apoptosis in AD cellular models through modulation of IFI16, suggesting that USP16 may serve as a promising therapeutic target for AD.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
This study identifies USP16 as a deubiquitylating enzyme of IFI16 and shows that USP16 depletion alleviates Aβ1–42-induced inflammation and neuronal apoptosis in cellular AD models. The effects appear mediated through IFI16 and the TLR4/NLRP3 signaling axis.
Key findings
- IFI16 was markedly upregulated in AD according to dataset GSE129296; silencing IFI16 attenuated Aβ1–42-induced proinflammatory responses in glial cells, reduced neuronal apoptosis, and enhanced neuronal viability, with decreased TNF-α and IL-1β levels and downregulation of TLR4/NLRP3 (p < 0.05).
- USP16 was identified as the deubiquitylating enzyme of IFI16, was significantly elevated in Aβ1–42-stimulated glial cells, and its silencing reduced IFI16 expression (p < 0.05).
- Co-immunoprecipitation and in vitro deubiquitylation assays showed ectopically expressed USP16 interacted with IFI16, and USP16 silencing enhanced IFI16 ubiquitination.
- IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation; USP16 silencing reduced TNF-α/IL-1β and TLR4/NLRP3 and reversed IFI16-induced neuronal damage (p < 0.05).
Methods
- Differentially expressed genes associated with AD were identified using dataset GSE129296 via GEO2R; Ubibrowser was used to predict deubiquitylating enzymes targeting IFI16.
- HMC3 glial cells were exposed to Aβ1–42 (5 µM for 24 h) to establish an in vitro AD model, then indirectly co-cultured with SH-SY5Y neuronal cells; HEK-293T cells were used for co-immunoprecipitation and in vitro deubiquitylation assays.
- Neuronal viability and apoptosis were assessed by CCK-8 and flow cytometry; TNF-α and IL-1β by ELISA; USP16/IFI16 and TLR4/NLRP3 expression by RT-qPCR and western blotting. Statistics used mean ± standard deviation, independent samples t-test or one-way ANOVA with Tukey post-hoc, with p < 0.05 considered significant.
Limitations
- Stated in the paper: the current study lacks in vivo validation to further validate the findings, which the authors say will be the focus of future investigations.
- Evident from the text: the experimental evidence is based on in vitro cell models (HMC3, SH-SY5Y, HEK-293T) and bioinformatic prediction, with no in vivo or human tissue validation reported.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 45 cited sources checked · 0 supported · 0 flagged
- Findingcitation
IFI16 is markedly upregulated/highly expressed in AD.
“IFI16 was markedly upregulated in AD.”
- Also stated in: § Introduction · plain
“interferon gammainducible protein 204 (IFI204), the murine homolog of interferon gamma-inducible protein 16 (IFI16), was found to be markedly elevated in AD [8].”
- Also stated in: § IFI16 Knockdown in Glial Cells Attenuated Aβ1-42-Induced Inflammation and Neuronal Apoptosis · plain
“where IFI16 was identified as highly expressed (Fig. 1A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: The GSE129296 dataset is representative of human AD for identifying differentially expressed genes.
- Also stated in: § Introduction · plain
- Findingown data
IFI16 overexpression reversed the effects of USP16 knockdown on apoptosis.
“Furthermore, IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation.”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
Overexpression of IFI16 significantly upregulated IL-1β secretion in Aβ1-42-induced glial cells.
“Both cytokines were significantly upregulated following the overexpression of IFI16 (Fig. 3A,B, p < 0.05)”
Quote in the paperSubstantial claim - Findingcitation
Among predicted deubiquitylating enzymes, only USP16 stood out.
“Among the predicted deubiquitylating enzymes, only ubiquitinspecific peptidase 16 (USP16) stood out”
Quote in the paperSubstantial claim- Rests on an assumption: Ubibrowser predictions reliably identify deubiquitylating enzymes targeting IFI16.
- Findingown data
In the co-culture system, modulation of USP16 and IFI16 expression in glial cells markedly affected neuronal survival.
“Moreover, in the co-culture system, modulation of USP16 and IFI16 expression in glial cells markedly affected neuronal survival.”
Quote in the paperSubstantial claim
- Findingown data
USP16 is highly expressed in AD.
“USP16 functions as the DUBs of IFI16 and is highly expressed in AD.”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42 exposure enhanced neuronal apoptosis in co-cultured SH-SY5Y cells.
“Exposure to Aβ1-42 markedly reduced neuronal viability and enhanced apoptosis (Fig. 1H-J, p < 0.05).”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: The indirect co-culture system adequately models neuron-glia interactions in AD.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
USP16 knockdown counteracted the effects of IFI16 overexpression on aggravating inflammation and neuronal apoptosis in Aβ1-42-induced AD model cells.
“USP16 knockdown counteracted the effects of IFI16 overexpression on aggravating inflammation and neuronal apoptosis in Aβ1-42-induced AD model cells.”
Quote in the paperSubstantial claim - Findingown data
USP16 expression significantly increased in HMC3 glial cells following Aβ1-42 induction.
“We then determined the expression level of USP16 in HMC3 glial cells following Aβ1-42 induction and observed a significant increase (Fig. 2B,C, p < 0.05).”
- Also stated in: § Abstract · plain
“USP16, identified as the deubiquitylating enzyme of IFI16, was significantly elevated in Aβ1-42-stimulated glial cells”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Also stated in: § Abstract · plain
- Findingown data
IFI16 was significantly upregulated in AD.
“Consistent with our experimental data, IFI16 was significantly upregulated in AD, and its overexpression aggravated inflammation in AD model cells, as evidenced by an increased apoptosis rate and elevated levels of proinflammatory cytokines (TNF-α and IL-1β) and TLR4/NLRP3 signaling components.”
Quote in the paperSubstantial claim - Findingown data
IFI16 overexpression significantly suppressed viability of SH-SY5Y cells in co-culture with HMC3 glial cells.
“IFI16 overexpression significantly suppressed the viability of SH-SY5Y cells and promoted apoptosis (Fig. 3F-H, p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
IFI16 is deubiquitinated by USP16.
“which was abnormally overexpressed in AD and deubiquitinated by USP16”
- Also stated in: § Conclusion · plain
“USP16 functions as the DUBs of IFI16 and is highly expressed in AD.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data
IFI16 silencing significantly restored neuronal viability in co-cultured SH-SY5Y cells.
“Conversely, IFI16 silencing significantly restored neuronal viability and inhibited apoptosis (Fig. 1H-J, p < 0.05).”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: The indirect co-culture system adequately models neuron-glia interactions in AD.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
Overexpression of IFI16 significantly upregulated TNF-α secretion in Aβ1-42-induced glial cells.
“Both cytokines were significantly upregulated following the overexpression of IFI16 (Fig. 3A,B, p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
USP16 silencing reversed the effects of IFI16 overexpression on viability and apoptosis of SH-SY5Y cells.
“whereas USP16 silencing reversed these effects (Fig. 3F-H, p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
USP16 silencing markedly reduced IFI16 expression in HMC3 glial cells.
“Moreover, following USP16 silencing, the expression level of IFI16 was markedly reduced (Fig. 2E,F, p < 0.05).”
- Also stated in: § Abstract · plain
“its silencing reduced IFI16 expression”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Also stated in: § Abstract · plain
- Findingown data
Silencing IFI16 attenuated inflammation and apoptosis in AD model cells.
“Based on our findings, we confirmed that silencing IFI16, which was abnormally overexpressed in AD and deubiquitinated by USP16, attenuated inflammation and apoptosis in AD model cells.”
- Also stated in: § Conclusion · plain
“Knockdown of IFI16, a gene abnormally overexpressed in AD, attenuates Aβ1-42-induced inflammation and neuronal apoptosis in glial cells.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data
IFI16 overexpression markedly enhanced protein levels of TLR4 in model HMC3 cells.
“IFI16 overexpression markedly enhanced the protein levels of TLR4 and NLRP3 within the model HMC3 cells (Fig. 3C-E, p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
IFI16 knockdown notably reduced inflammation-related markers (TNF-α, IL-1β, TLR4, NLRP3) in Aβ1-42-exposed HMC3 glial cells.
“whereas their expression was notably reduced after IFI16 knockdown (Fig. 1C-G, p < 0.05).”
- Also stated in: § Abstract · plain
“Silencing of IFI16 attenuated Aβ1-42-induced proinflammatory responses in glial cells, reduced neuronal apoptosis, and enhanced neuronal viability, accompanied by decreased inflammatory cytokine levels and downregulation of TLR4/NLRP3 expression.”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Also stated in: § Abstract · plain
- Findingown data
IFI16 is abnormally overexpressed in AD.
“which was abnormally overexpressed in AD”
- Also stated in: § Conclusion · plain
“Knockdown of IFI16, a gene abnormally overexpressed in AD, attenuates Aβ1-42-induced inflammation and neuronal apoptosis in glial cells.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data
IFI16 silencing significantly inhibited neuronal apoptosis in co-cultured SH-SY5Y cells.
“Conversely, IFI16 silencing significantly restored neuronal viability and inhibited apoptosis (Fig. 1H-J, p < 0.05).”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: The indirect co-culture system adequately models neuron-glia interactions in AD.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
IFI16 overexpression reversed the effects of USP16 knockdown on cell survival.
“Furthermore, IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation.”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
IFI16 overexpression reversed the effects of USP16 knockdown on inflammation.
“Furthermore, IFI16 overexpression reversed the effects of USP16 knockdown on cell survival, apoptosis, and inflammation.”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
Silencing of USP16 enhanced IFI16 ubiquitination.
“and that the silencing of USP16 enhanced IFI16 ubiquitination (Fig. 2G,H).”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42 exposure markedly reduced neuronal viability in co-cultured SH-SY5Y cells.
“Exposure to Aβ1-42 markedly reduced neuronal viability and enhanced apoptosis (Fig. 1H-J, p < 0.05).”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: The indirect co-culture system adequately models neuron-glia interactions in AD.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
IFI16 overexpression markedly enhanced protein levels of NLRP3 in model HMC3 cells.
“IFI16 overexpression markedly enhanced the protein levels of TLR4 and NLRP3 within the model HMC3 cells (Fig. 3C-E, p < 0.05)”
Quote in the paperSubstantial claim - Findingown data
Aβ1-42 exposure significantly elevated inflammation-related markers (TNF-α, IL-1β, TLR4, NLRP3) in HMC3 glial cells.
“These inflammation-related markers were significantly elevated following Aβ1-42 exposure (Fig. 1C-G, p < 0.05)”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Findingown data
IFI16 overexpression promoted apoptosis of SH-SY5Y cells in co-culture with HMC3 glial cells.
“IFI16 overexpression significantly suppressed the viability of SH-SY5Y cells and promoted apoptosis (Fig. 3F-H, p < 0.05)”
Quote in the paperSubstantial claim - Premisecitation
IFI16 regulates inflammatory processes in AD.
“Interferon gamma-inducible protein 16 (IFI16) regulates inflammatory processes in AD”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
The pathogenesis of AD involves strong interactions with immunological mechanisms within the brain.
“the pathogenesis of AD is not only confined to the neuronal compartment but also involves strong interactions with immunological mechanisms within the brain [6].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The interaction between USP16 and IFI16 through deubiquitylation modulates inflammation and apoptosis in Aβ1-42-induced cellular AD models.
“In summary, our findings indicate that the interaction between USP16 and IFI16 through deubiquitylation modulates inflammation and apoptosis in Aβ1-42-induced cellular AD models.”
Quote in the paperSubstantial claim - Interpretationown data
IFI16 contributes to the aggravation of AD through promotion of neuroinflammatory and apoptotic processes.
“These findings collectively support the hypothesis that IFI16 contributes to the aggravation of AD through promotion of neuroinflammatory and apoptotic processes.”
Quote in the paperSubstantial claim - Premisecitation
IFI16 modulates inflammatory processes.
“Moreover, IFI16 has been shown to mediate TNFα-induced expression of Intercellular Adhesion Molecule 1 (ICAM-1), modulate inflammatory processes, and aggravate LPS-induced TLR4-mediated inflammation, while impacting NLRP3 inflammasome activation to promote inflammation in response to Kaposi's sarcoma-associated herpesvirus infection [37][38][39].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
USP16 is the deubiquitylating enzyme of IFI16.
“USP16, identified as the deubiquitylating enzyme of IFI16”
Quote in the paperSubstantial claim- Rests on an assumption: Ubibrowser predictions reliably identify deubiquitylating enzymes targeting IFI16.
- Interpretationown data
USP16 depletion alleviates inflammation and apoptosis in AD cellular models through modulation of IFI16.
“USP16 depletion alleviates inflammation and apoptosis in AD cellular models through modulation of IFI16”
Quote in the paperSubstantial claim- Rests on an assumption: The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
- Rests on an assumption: The indirect co-culture system adequately models neuron-glia interactions in AD.
- Rests on an assumption: Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
- Interpretationown data
The USP16/IFI16 axis has a regulatory role in AD pathogenesis.
“These results highlight the regulatory role of the USP16/IFI16 axis in AD pathogenesis and contribute to elucidating the underlying molecular mechanisms involved.”
Quote in the paperSubstantial claim - Study design and conductown data
sh#2 achieved the most effective knockdown of IFI16.
“The data revealed that sh#2 achieved the most effective knockdown (Fig. 1B, p < 0.05).”
Quote in the paperSubstantial claim - Interpretationreasoning
USP16 may serve as a promising therapeutic target for AD.
“suggesting that USP16 may serve as a promising therapeutic target for AD.”
Quote in the paperSubstantial claim- Rests on an assumption: In vitro findings in cell lines can be extrapolated to AD pathophysiology in vivo.
- Premisecitation
Inflammation within glial cells is a crucial factor that disrupts homeostasis and exacerbates AD progression.
“Glial cells are vital for sustaining brain homeostasis and play pivotal roles in central nervous system (CNS) injury and diseases, and the inflammation within these cells has been recognized as a crucial factor that disrupts homeostasis and exacerbates AD progression [28,29].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
The regulatory effect of USP16/IFI16 on inflammation and apoptosis appears to be mediated through modulation of the TLR4/NLRP3 inflammasome signaling axis.
“This regulatory effect appears to be mediated through the modulation of the TLR4/NLRP3 inflammasome signaling axis.”
Quote in the paperSubstantial claim
- It may state two separate claims as one. 17
- Probably not a substantial claim. 28
It may state two separate claims as one.
Findingown dataUSP16 knockdown reduced TLR4 levels and mitigated IFI16-induced TLR4 overexpression in HMC3 cells.
“while USP16 knockdown exerted the opposite effect and mitigated the IFI16-induced overexpression (Fig. 3C-E, p < 0.05)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSilencing of USP16 reduced IL-1β levels and reversed the proinflammatory effects of IFI16 overexpression on IL-1β in Aβ1-42-induced glial cells.
“while silencing of USP16 reduced their levels and reversed the proinflammatory effects of IFI16 overexpression (Fig. 3A,B, p < 0.05)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSilencing of USP16 reduced TNF-α levels and reversed the proinflammatory effects of IFI16 overexpression on TNF-α in Aβ1-42-induced glial cells.
“while silencing of USP16 reduced their levels and reversed the proinflammatory effects of IFI16 overexpression (Fig. 3A,B, p < 0.05)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIFI16 overexpression aggravated inflammation in AD model cells, as evidenced by increased apoptosis rate and elevated levels of proinflammatory cytokines (TNF-α and IL-1β) and TLR4/NLRP3 signaling components.
“Consistent with our experimental data, IFI16 was significantly upregulated in AD, and its overexpression aggravated inflammation in AD model cells, as evidenced by an increased apoptosis rate and elevated levels of proinflammatory cytokines (TNF-α and IL-1β) and TLR4/NLRP3 signaling components.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataUSP16 knockdown reduced NLRP3 levels and mitigated IFI16-induced NLRP3 overexpression in HMC3 cells.
“while USP16 knockdown exerted the opposite effect and mitigated the IFI16-induced overexpression (Fig. 3C-E, p < 0.05)”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationUSP16 inhibition ameliorates memory deficits in an AD model.
“inhibition of USP16 has been reported to rescue stem cell aging and ameliorate memory deficits in an AD model [18].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationUbiquitin modulates various aspects of protein fate and function, including protein degradation via the UPS.
“ubiquitin has been shown to modulate various aspects of protein fate and function, including protein degradation via the UPS [15].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
PremisecitationIFI16 plays a pivotal role in canonical LPS-induced TLR4 signaling, which can bind to Aβ and activate downstream NLRP3, thereby amplifying inflammation in AD.
“IFI16 (also known as p204) plays a pivotal role in canonical lipopolysaccharide (LPS)-induced toll-like receptor 4 (TLR4) signaling, which can bind to Aβ and activate downstream intracellular signaling cascades such as NLR family pyrin domain containing 3 (NLRP3), thereby amplifying inflammation in AD [9][10][11].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCommunication between neurons and glial cells is essential for maintaining synaptic homeostasis.
“communication between neurons and glial cells is essential for maintaining synaptic homeostasis and may be disrupted during AD progression [7].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
PremisecitationNeuroinflammation plays a role in neurodegenerative diseases such as AD.
“Growing evidence has underscored the role of neuroinflammation in neurodegenerative diseases (NDs) such as AD [5].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationUPS dysfunction contributes to the accumulation of phosphorylated tau (p-tau) in AD.
“disruption of the ubiquitin-proteasome system (UPS) in AD has been observed, wherein UPS dysfunction contributes to the accumulation of phosphorylated tau (p-tau), an underappreciated marker of AD [14].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
PremisecitationDUBs have emerged as promising therapeutic targets in neurodegenerative diseases, including AD, due to their roles in modulating the stability of NDs-associated pathological proteins.
“DUBs have emerged as promising therapeutic targets in neurodegenerative diseases (NDs), including AD, due to their roles in modulating the stability of NDs-associated pathological proteins [16,17].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationCommunication between neurons and glial cells may be disrupted during AD progression.
“communication between neurons and glial cells is essential for maintaining synaptic homeostasis and may be disrupted during AD progression [7].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationDUBs counterregulate the ubiquitination process and influence the stability of neurodegeneration-related pathogenic proteins.
“Moreover, DUBs have been shown to counterregulate the ubiquitination process and influence the stability of neurodegeneration-related pathogenic proteins [17].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAβ1-42 present in cerebrospinal fluid is widely recognized as a central biomarker for AD severity, suggesting its potential as a diagnostic marker for AD.
“Notably, Aβ1-42 present in cerebrospinal fluid (CSF) has been widely recognized as a central biomarker for AD severity, suggesting its potential as a diagnostic marker for the disease [24].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [24]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductown dataIFI16 overexpression plasmid increased IFI16 expression, confirming transfection efficiency.
“with increased IFI16 expression confirming transfection efficiency (Fig. 2I, p < 0.05).”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIFI16 induces inflammation in hepatitis B virus-associated glomerulonephritis through modulation of the caspase-1/IL-1β pathway.
“Previous studies have shown that IFI16 induces inflammation in hepatitis B virus-associated glomerulonephritis through modulation of the caspase-1/IL-1β pathway and mediates STING signaling as a crucial regulator of anti-HER2 immune responses in HER2-positive breast cancer [35,36].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIFI16 aggravates LPS-induced TLR4-mediated inflammation.
“Moreover, IFI16 has been shown to mediate TNFα-induced expression of Intercellular Adhesion Molecule 1 (ICAM-1), modulate inflammatory processes, and aggravate LPS-induced TLR4-mediated inflammation, while impacting NLRP3 inflammasome activation to promote inflammation in response to Kaposi's sarcoma-associated herpesvirus infection [37][38][39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAβ is produced through cleavage of amyloid precursor protein in the cell membrane by β-secretase and γ-secretase, generating monomeric peptides of varying lengths.
“Aβ is produced through the cleavage of amyloid precursor protein in the cell membrane by β-secretase and γ-secretase, generating monomeric peptides of varying lengths [23].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIFI16 mediates STING signaling as a crucial regulator of anti-HER2 immune responses in HER2-positive breast cancer.
“Previous studies have shown that IFI16 induces inflammation in hepatitis B virus-associated glomerulonephritis through modulation of the caspase-1/IL-1β pathway and mediates STING signaling as a crucial regulator of anti-HER2 immune responses in HER2-positive breast cancer [35,36].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [36]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDUBs are key participants in the ubiquitin-proteasome system, where they regulate disease-associated proteins by modulating the degree of ubiquitination.
“Enzymes, including the DUBs, have been emphasized as key participants in the UPS, where they regulate diseaseassociated proteins by modulating the degree of ubiquitination [41].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationNeuroinflammation, characterized by glial cell activation, is often indicated by increased expression of inflammatory cytokines including TNF-α and IL-1β, both early response markers expressed concurrently.
“Additionally, neuroinflammation, characterized by glial cell activation, is often indicated by increased expression of inflammatory cytokines, including TNF-α and IL-1β, both of which are early response markers and are expressed concurrently [30].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataThe current study lacks in vivo validation.
“However, the current study lacks an in vivo validation to further validate these findings, which will be the focus of future investigations.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper may give no reason why it holds.
InterpretationreasoningUSP16 may aggravate neuroinflammation in AD through deubiquitination of IFI16, thereby enhancing its stability.
“We therefore propose that USP16 may aggravate neuroinflammation in AD through deubiquitination of IFI16, thereby enhancing its stability.”
Quote in the paperNot a substantial claimProbably not a substantial claim. It may state two separate claims as one.
PremisecitationActivation of the TLR4 signaling pathway initiates neuroinflammation, with the NLRP3 inflammasome serving as a key mediator.
“Mechanistically, activation of the TLR4 signaling pathway has been reported to initiate neuroinflammation, with the NLRP3 inflammasome serving as a key mediator [33,34].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone givenCell lines were tested for mycoplasma contamination, confirmed free, and authenticated using STR analysis.
“All lines were tested for mycoplasma contamination, confirmed to be free of contamination, and were authenticated using short tandem repeat (STR) analysis.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationUSP16 has potential roles in stabilizing c-Myc, histone H2A lysine-119, and calcineurin A.
“Notably, in addition to their potential roles in stabilizing c-Myc [42], histone H2A lysine-119 [43], and calcineurin A [44], USP16 knockdown has been reported to rescue stem cell aging and memory deficits in AD models [18].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationThe interaction between neurons and glial cells in AD pathogenesis is crucial for maintaining synaptic homeostasis.
“Moreover, the interaction between neurons and glial cells in AD pathogenesis has been identified as crucial for maintaining synaptic homeostasis [7,27].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGlial cells are vital for sustaining brain homeostasis and play pivotal roles in central nervous system injury and diseases.
“Glial cells are vital for sustaining brain homeostasis and play pivotal roles in central nervous system (CNS) injury and diseases, and the inflammation within these cells has been recognized as a crucial factor that disrupts homeostasis and exacerbates AD progression [28,29].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [28]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [29]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationUSP16 knockdown rescues stem cell aging and memory deficits in AD models.
“Notably, in addition to their potential roles in stabilizing c-Myc [42], histone H2A lysine-119 [43], and calcineurin A [44], USP16 knockdown has been reported to rescue stem cell aging and memory deficits in AD models [18].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAD is a complex neurodegenerative disorder, with accumulating evidence indicating that both glial and neuronal cells play significant roles in its pathogenesis.
“AD is a complex neurodegenerative disorder, with accumulating evidence indicating that both glial and neuronal cells play significant roles in its pathogenesis [25,26].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [26]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIFI16 mediates TNFα-induced expression of Intercellular Adhesion Molecule 1 (ICAM-1).
“Moreover, IFI16 has been shown to mediate TNFα-induced expression of Intercellular Adhesion Molecule 1 (ICAM-1), modulate inflammatory processes, and aggravate LPS-induced TLR4-mediated inflammation, while impacting NLRP3 inflammasome activation to promote inflammation in response to Kaposi's sarcoma-associated herpesvirus infection [37][38][39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGlial cells regulate synapse formation and respond to neural activity.
“Among their diverse functions, glial cells regulate synapse formation and respond to neural activity, suggesting that impaired neuron-glia interactions may contribute to the pathogenesis of neurodevelopmental disorders [31,32].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIFI16 impacts NLRP3 inflammasome activation to promote inflammation in response to Kaposi's sarcoma-associated herpesvirus infection.
“Moreover, IFI16 has been shown to mediate TNFα-induced expression of Intercellular Adhesion Molecule 1 (ICAM-1), modulate inflammatory processes, and aggravate LPS-induced TLR4-mediated inflammation, while impacting NLRP3 inflammasome activation to promote inflammation in response to Kaposi's sarcoma-associated herpesvirus infection [37][38][39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
The paper relies on this without support.
The GSE129296 dataset is representative of human AD for identifying differentially expressed genes.
“The dataset GSE129296 was first employed to analyze differentially expressed genes (DEGs) in AD”
The paper relies on this without support.
The HMC3 glial cell line and SH-SY5Y neuronal cell line are valid models for studying AD glial and neuronal responses.
“The human glial cell line HMC3 (CRL-3304) and the neuronal cell line SH-SY5Y (CRL-2266) were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).”
The paper relies on this without support.
The indirect co-culture system adequately models neuron-glia interactions in AD.
“To investigate the influence of glial cells on neuronal function, an indirect co-culture system was established using Transwell inserts”
The paper relies on this without support.
Ubibrowser predictions reliably identify deubiquitylating enzymes targeting IFI16.
“Additionally, Ubibrowser (http://ubibrowser.bio-it.cn /ubibrowser_v3/) was adopted to predict potential deubiquitylation enzymes targeting IFI16”
The paper relies on this without support.
Aβ1-42 treatment at 5 µM for 24 h in HMC3 cells adequately mimics AD-related glial activation.
“Based on previous studies [19], treatment with 5 µM Aβ1-42 for 24 h was performed for subsequent experiments.”
The paper relies on this without support.
In vitro findings in cell lines can be extrapolated to AD pathophysiology in vivo.
“suggesting that USP16 may serve as a promising therapeutic target for AD.”
The paper relies on this without support.
The precise role and mechanisms of IFI16 in AD pathogenesis remain insufficiently elucidated.
“Nevertheless, the precise role and mechanisms of IFI16 in AD pathogenesis remain insufficiently elucidated.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Dilution is said to increase Aβ1-42 concentration
MajorThe preparation starts with a 5 μM peptide solution, then says dilution with PBS produces a 400 μM solution. Dilution alone cannot raise the concentration eightyfold.
“The resulting, peptide film was resuspended to a concentration of 5 µM in anhydrous dimethyl sulfoxide (DMSO, D12345, ThermoFisher Scientific, USA)”
“and subsequently diluted with phosphate-buffered saline (PBS, AC13317, Acmec Biochemical, China) to a final concentration of 400 µM”
Section heading assigns USP16 the opposite inflammatory role
MinorThe heading says USP16 antagonized IFI16-mediated inflammation, but the section reports that knocking down USP16 reduced inflammation and reversed the proinflammatory effects of IFI16 overexpression.
“USP16 Antagonized IFI16-Mediated Inflammation and Neuronal Damage”
“Both cytokines were significantly upregulated following the overexpression of IFI16 (Fig. 3A,B, p < 0.05), while silencing of USP16 reduced their levels and reversed the proinflammatory effects of IFI16 overexpression (Fig. 3A,B, p < 0.05).”
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Cited by
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Shabnam, F., Singh, M., Amin, R., & Griffett, K. (2026) · British Journal of Biomedical Science · doi:10.3389/bjbs.2026.16121
Metadata
- Authors
- Cui, B., Ding, Y., & Li, C.
- Affiliations
- Capital Medical University (CN)
- ORCID
- Cui, Bo
- Venue
- Discovery Medicine
- Publisher
- Discovery Medicine
- Published
- 2025
- Volume
- 37
- Issue
- 203
- Pages
- 2932
- ISSN
- 1539-6509 (ISSN-L)
- OpenAlex
- W4417488317
- Semantic Scholar
- 78b80c011da782c4874c4222edd4ea90d5f5129e
- Cited by
- 1
- References
- 31
- Citations by year
- 2026: 1
- FWCI
- 0.30
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Discovery Medicine (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Keywords
- Alzheimer's disease, USP16, IFI16, amyloid-beta 42, neuroinflammation, deubiquitination, glial cells, neuronal apoptosis, TNF-α, IL-1β, therapeutic target, neuroprotection, memory impairment, ubiquitination
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