CoChat
Sign Up
Cited by 4Neuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and TreatmentsAlzheimer's disease research and treatments

The DOI matches its Crossref record; 67 of the 67 references it cites were found in a registry or an index; 8 of the 76 sources its claims cite were checked for support.

MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity

Open access
Asthana, Pallavi, Li, Liguo, Lu, Lin, Wu, Jiayan, Zhang, Shuo, Li, Ningning, Wong, Sheung Kin Ken, Gurung, Susma, Zhang, Yijing, Lin, Yuwan, Peng, Yufeng, Xu, Zongtang, Chan, Kui Ming, Zhai, Lixiang, Lyu, Aiping, Bian, Zhao-Xiang, Ge, Xin, Iyaswamy, Ashok, Li, Min, Su, Ya, Zhou, Zhongjun, Xu, Pingyi, Wong, Hoi Leong Xavier·2025·Cell Discovery
DOI 10.1038/s41421-025-00825-wPMC PMC12454644
Open this paper in CoChat — free accountOpen PDF

Abstract

Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In mice and human hippocampal transcriptome data, age- and obesity-related neuroinflammation increases hippocampal MT1-MMP, which proteolytically cleaves GPR158 and suppresses osteocalcin/GPR158-dependent cognition. Genetic or pharmacological MT1-MMP blockade restores memory, synaptic plasticity, and metabolic parameters in aged and obese mice without altering neuroinflammation.

Key findings

  • Hippocampal MT1-MMP expression and activity increased in 18-month-old versus 2-month-old mice; MMP14 was elevated in older human hippocampus (GTEx/HPA) and positively correlated with neuroinflammatory markers including NF-κB, IL1B, IL6, CCL3, IL23A, CD11B, TNF, and C1QB.
  • MT1-MMP activation alone was sufficient to impair cognition: AAV-WT MT1-MMP in 2-month-old hippocampus impaired object location, Barnes maze, contextual fear, and LTP, whereas catalytically inactive MT1-EA did not. Conversely, Mmp14 haploinsufficiency or hippocampal shRNA reversed age-related memory and LTP deficits without changing neuroinflammation or blood-brain barrier integrity.
  • Oral Ro 28-2653 (50 mg/kg every 2 days from 20 to 21 months) improved Y-maze and contextual fear memory, body weight/lean mass, glucose and insulin tolerance, and liver AST/ALT/TG in aged mice; intrahippocampal 3A2 antibody also improved memory. In HFD-induced obesity, hippocampal MT1-MMP knockdown or Ro 28-2653 improved memory/LTP and metabolic parameters.
  • Mechanistically, MT1-MMP cleaved GPR158: Mmp14 deficiency increased hippocampal and primary-neuron GPR158 protein, aged and HFD mice had reduced GPR158, and MT1-MMP cleavage suppressed OCN-induced IP3 accumulation and OCN’s cognition-promoting effects; hippocampal Gpr158 knockdown abolished the cognitive benefits of Mmp14 heterozygosity.

Methods

  • Male C57BL/6J mice were used, including young (2–3 months), aged (18/20/24 months), Mmp14+/−, Mmp2−/−, Mmp9−/−, and HFD (60% kcal fat) versus chow diet (10% kcal fat) models. Interventions included hippocampal lentiviral/AAV injections, osmotic-pump antibody infusion, oral C52 or Ro 28-2653, and aged-plasma infusion.
  • Cognition and plasticity were assessed with object location, Barnes maze, contextual fear conditioning, Y-maze, Morris water maze, open field, wire hang, nesting, and gait tests, plus CA1 LTP electrophysiology. Molecular analyses included western blotting, qPCR, ELISA, Luminex cytokine assays, MMP14 activity assays, Evans blue BBB permeability, primary hippocampal cultures, and in vitro GPR158 cleavage assays.
  • Human data came from GTEx/HPA hippocampal transcriptomes, comparing young (20–39 years) and aged (70–79 years) donors and correlating MMP14 with pro-inflammatory markers. Statistics used GraphPad Prism, mean ± SEM, P < 0.05, and ANOVA with post hoc tests.

Limitations

  • Stated: further investigation is required to validate the safety of MT1-MMP inhibition; the precise mechanisms by which TIMP2 enhances cognition during aging remain unresolved; clinical translation of MMP inhibitors is challenged by context-dependent MMP roles.
  • Evident from the text: mouse experiments used male C57BL/6J mice only, so sex-specific effects are not addressed; human evidence is correlational transcriptomic data, not causal; Ro 28-2653 also inhibits MMP2 and MMP9, although the authors argue MMP2/MMP9 knockouts did not alter aged memory.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41421-025-00825-w

Cites

67 of 67 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

8 of 76 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Mmp14 haploinsufficient (Mmp14+/−) mice do not display gross postnatal phenotypes.

    “Mmp14 haploinsufficient (Mmp14+/−) mice, which do not display gross postnatal phenotypes24–26.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [24] Zhou, Z. et al. Impaired endochondral ossification and angiogenesis in mice deficient in membrane-type matrix metalloproteinase I. Proc. Natl. Acad. Sci. USA 97, 4052–4057 (2000). source
    • cites [25] Holmbeck, K. et al. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover. Cell 99, 81–92 (1999). source
    • cites [26] Chan, K. M. et al. MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis. Dev. Cell 22, 1176–1190 (2012). source
  • Findingown data

    Only aged Mmp14+/− mice exhibited significant improvements in learning and memory among aged Mmp2−/−, Mmp9−/−, and Mmp14+/− mice.

    “We found that only aged Mmp14+/− mice exhibited significant improvements in learning and memory (Supplementary Fig. S7a–c)”
    Quote in the paperSubstantial claim
  • Findingown data

    Treatment with Ro 28-2653 improved spatial memory and cognition in mice with HFD-induced obesity.

    “Through the object location memory task, the Y-maze test, and the water maze test, we found that treatment with Ro 28-2653 improved spatial memory and cognition in mice with HFD-induced obesity (Supplementary Fig. S8b–e).”
    Quote in the paperSubstantial claim
  • Findingown data

    Impaired glucose metabolism in aged mice, as assessed by GTT and ITT, was mitigated by the treatment of Ro 28-2653.

    “Impaired glucose metabolism in aged mice, as assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT), was similarly mitigated by the treatment of Ro 28-2653 (Fig. 4d, e).”
    Quote in the paperSubstantial claim
  • Findingown data

    There were no changes in microglia activation in the hippocampus of 18-month-old aged Mmp14+/− mice.

    “Flow cytometry analyses revealed that there were also no changes in microglia activation in the hippocampus of 18-month-old aged Mmp14+/− mice (Supplementary Fig. S2l–n).”
    Quote in the paperSubstantial claim
  • Probably not a substantial claim. 28
  • It may state two separate claims as one. 46

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    Inflammaging in the brain is characterized by increased levels of proinflammatory cytokines, aberrant activation of astrocytes and microglia, and increased oxidative stress.

    “Inflammaging in the brain is characterized by increased levels of proinflammatory cytokines, aberrant activation of astrocytes and microglia, and increased oxidative stress2–4.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [2] Harry, G. J. Microglia during development and aging. Pharm. Ther. 139, 313–326 (2013). source

      The Introduction links aging to elevated proinflammatory cytokines, changes in microglial activation, and oxidative stress; Section 6 also reports elevated basal proinflammatory cytokines in the aged brain. The passages do not establish aberrant astrocyte activation as a feature of brain aging, and the Introduction describes the microglial contribution to oxidative stress as a possibility rather than an established increase. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [3] Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharm. 88, 594–604 (2014). source

      Section 4.4 reports that proinflammatory-factor release from aged microglia is generally increased, that microglial activation changes with aging, and that oxidative stress increases in aging. The passages do not establish aberrant activation of astrocytes as part of this pattern; the paper also cautions that cytokine release depends on the stimulus and microglial activation states are difficult to generalize. Page numbers were not available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [4] Safaiyan, S. et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016). source

      The passage on microglial senescence (section labeled Abstract; page unavailable) describes low-grade microglial activation, and the cuprizone experiment reports age-associated immune activation. The copy does not substantiate the other attributed features: increased proinflammatory cytokines, aberrant astrocyte activation, or increased oxidative stress. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Increasing evidence has suggested that neuroinflammation is a major contributor to cognitive impairment.

    “In recent years, increasing evidence has suggested that neuroinflammation is a major contributor to cognitive impairment2–4.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [2] Harry, G. J. Microglia during development and aging. Pharm. Ther. 139, 313–326 (2013). source

      The Introduction (page not available) links age-related inflammatory changes in microglia to a possible impact on synaptic plasticity and cognitive function. It does not establish that neuroinflammation is a major contributor to cognitive impairment generally; its discussion is narrower and more tentative. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [3] Mosher, K. I. & Wyss-Coray, T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharm. 88, 594–604 (2014). source

      The Conclusion (page not available) suggests that chronic inflammation could drive dysfunctional microglia, eventually leading to neurodegeneration and sometimes Alzheimer’s disease. Section 4.4 also describes neuronal damage from excessive proinflammatory activity. The paper does not establish neuroinflammation as a major contributor to cognitive impairment broadly; its discussion is focused on aging and Alzheimer’s disease. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites [4] Safaiyan, S. et al. Age-related myelin degradation burdens the clearance function of microglia during aging. Nat. Neurosci. 19, 995–998 (2016). source

      The paper’s Abstract reports age-related microglial immune activation and dysfunction, but does not connect either to cognitive impairment. Searches for cognition, cognitive decline, and the proposed neuroinflammation–impairment link found no passage addressing that relationship; the paper also does not assess whether neuroinflammation is a major contributor. (LLM, conf=0.74)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    ECM remodeling is regulated by various enzymes, especially matrix metalloproteinases (MMPs).

    “ECM remodeling is regulated by various enzymes, especially matrix metalloproteinases (MMPs)10.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect. Biol 3, a005058 (2011). source

  • It may state two separate claims as one.

    Findingown data

    Mice receiving Ro 28-2653 at the dosage of 50 mg/kg/2 days from 20 months to 21 months of age exhibited improved spatial memory in the forced-alternation Y-maze test and enhanced associate memory in the contextual-fear-conditioning test.

    “Compared with 4-month-old control mice group, mice receiving Ro 28-2653 at the dosage of 50 mg/kg/2 days from 20 months to 21 months of age exhibited improved spatial memory in the forced-alternation Y-maze test (Fig. 4a) and enhanced associate memory in the contextual-fear-conditioning test (Fig. 4b).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Treatment of aged mice with C52 for one month restored the expression of proinflammatory factors, including Tnf, Cd11b, Il1b and Nfkb1, and the level of Mmp14 in the hippocampus to the corresponding levels in two-months-old (young) mice.

    “Treatment of aged mice with C52 for one month restored the expression of proinflammatory factors, including Tnf, Cd11b, Il1b and Nfkb1 (Supplementary Fig. S1), and the level of Mmp14 (Fig. 1e) in the hippocampus to the corresponding levels in two-months-old (young) mice”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity.

    “Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity.

    “Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Consumption of HFD for 11 weeks impaired LTP in HFD/shControl mice, and this effect was abrogated in HFD/shMMP14 mice.

    “Moreover, electrophysiological recordings in brain slice preparations showed that consumption of HFD for 11 weeks impaired LTP in HFD/shControl mice, and this effect was abrogated in HFD/shMMP14 mice (Supplementary Fig. S5j, k).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Targeted depletion of hippocampal MT1-MMP restored memory functions in HFD mice to levels observed in CD/shControl mice without altering inflammatory responses in the hippocampus.

    “The targeted depletion of hippocampal MT1-MMP restored memory functions in HFD mice to levels observed in CD/shControl mice without altering inflammatory responses in the hippocampus (Supplementary Fig. S5f–i).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Depletion of hippocampal MT1-MMP in aged mice reversed hippocampus-dependent memory deficits in the object location memory task and the Barnes maze task, restoring these functions to the levels observed in 2-month-old (young) mice.

    “Consistent with the results obtained from Mmp14+/− mice, depletion of hippocampal MT1-MMP in aged mice reversed hippocampus-dependent memory deficits in the object location memory task (Fig. 3a) and the Barnes maze task (Fig. 3b, c), restoring these functions to the levels observed in 2-month-old (young) mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingcitation

    HFD-induced obesity led to increased expression of hippocampal MT1-MMP, which was reversed by the lentivirus-mediated knockdown of MT1-MMP.

    “In line with our previous findings15, HFD-induced obesity led to increased expression of hippocampal MT1-MMP, which was reversed by the lentivirus-mediated knockdown of MT1-MMP (Supplementary Fig. S5b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). source

  • It may state two separate claims as one.

    Findingown data

    The performance of aged Mmp14+/− mice in both tasks was markedly improved and became indistinguishable from that of young mice of either genotype.

    “the performance of aged Mmp14+/− mice in both tasks was markedly improved and became indistinguishable from that of young mice of either genotype (Fig. 2b, d, e).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The increases in serum AST, ALT, and liver triglycerides observed in aged mice were suppressed by the treatment of Ro 28-2653, indicative of improved liver functions resulting from MT1-MMP inhibition.

    “The increases in serum aspartate aminotransferase (AST), Alanine Aminotransferase (ALT), and liver triglycerides (TG) observed in aged mice were suppressed by the treatment of Ro 28-2653 (Fig. 4f–h), indicative of improved liver functions resulting from MT1-MMP inhibition.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    There were no significant differences in Evan's blue diffusion in the hippocampus and the expression of major genes involved in the maintenance of BBB permeability and architecture because of MT1-MMP depletion.

    “We did not observe any significant differences in Evan’s blue diffusion in the hippocampus (Supplementary Fig. S6a) and the expression of major genes involved in the maintenance of BBB permeability and architecture because of MT1-MMP depletion (Supplementary Fig. S6b–d)”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The freezing level was significantly greater in 18-month-old Mmp14+/− mice during the hippocampus-dependent contextual memory task, indicating improved contextual memory in Mmp14+/− mice during aging.

    “In addition, the freezing level was significantly greater in 18-month-old Mmp14+/− mice during the hippocampus-dependent contextual memory task (Fig. 2f, g), indicating improved contextual memory in Mmp14+/− mice during aging.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Repeated infusions of plasma from 24-month-old aged mice, but not 2-month-old young mice, for four weeks induced a significant increase in MT1-MMP expression in the hippocampus and elicited cognitive deficits in 2-month-old young WT mice.

    “We found that repeated infusions of plasma from 24-month-old aged mice, but not 2-month-old young mice, for four weeks induced a significant increase in MT1-MMP expression in the hippocampus and elicited cognitive deficits in 2-month-old young WT mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    HFD consumption increased circulating levels of several pro-inflammatory cytokines, including IL1B, IL6, and TNFα, and this effect was comparable between HFD/shMMP14 and HFD/shControl mice.

    “Analyses of cytokines in the hippocampus and serum revealed that HFD consumption increased circulating levels of several pro-inflammatory cytokines, including IL1B, IL6, and TNFα, and this effect was comparable between HFD/shMMP14 and HFD/shControl mice (Supplementary Fig. S5d, e).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    3A2-treated mice exhibited improved spatial memory in the forced-alternation Y-maze test and improved associative memory in the contextual fear conditioning test.

    “Surprisingly, 3A2-treated mice exhibited improved spatial memory in the forced-alternation Y-maze test (Fig. 4i) and improved associative memory in the contextual fear conditioning test (Fig. 4j).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Incubation of recombinant human GPR158 with the recombinant catalytic domain of MT1-MMP reduced full-length GPR158 and produced a truncated form of GPR158.

    “The expression of full-length GPR158 was reduced concomitantly with the formation of a truncated form of GPR158 in the presence of rMT1.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Local delivery of OCN improved hippocampus-dependent memory in control mice and in mice injected with AAV-MT1-EA.

    “The local delivery of OCN improved hippocampus-dependent memory in both the control mice and mice injected with AAV-MT1-EA as observed in the novel object location task (Fig. 6n) and Barnes maze task (Fig. 6o–q).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Ectopic expression of WT MT1-MMP in the hippocampus of 2-month-old young mice impaired hippocampus-dependent spatial memory, whereas the catalytically inactive MT1-MMP mutant did not.

    “we found that the ectopic expression of WT MT1-MMP, but not the catalytically inactive MT1-MMP mutant, impaired hippocampus-dependent spatial memory in the young mice.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Haplodeficiency in MT1-MMP improved memory and synaptic plasticity in obese mice.

    “In contrast, haplodeficiency in MT1-MMP improved memory and synaptic plasticity in obese mice (Supplementary Fig. S12a–e).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Hippocampal MT1-MMP negatively regulates cognitive function in both aging and obesity, and this effect can be reversed by pharmacological MT1-MMP inhibition.

    “suggesting that hippocampal MT1-MMP negatively regulates cognitive function in both aging and obesity, and this effect can be reversed by pharmacological MT1-MMP inhibition.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Aging leads to dramatic changes in cognitive and neuronal function, the decline of which contributes to the development of neurological disorders.

    “Aging leads to dramatic changes in cognitive and neuronal function, the decline of which contributes to the development of neurological disorders1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Wyss-Coray, T. Ageing, neurodegeneration and brain rejuvenation. Nature 539, 180–186 (2016). source

  • It may state two separate claims as one.

    Premisenone given

    Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol.

    “Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    In the brain, the ECM is particularly important for maintaining the structural integrity of neural tissues and homeostatic neuronal processes, including synaptic functions.

    “In the brain, the ECM is particularly important for maintaining the structural integrity of neural tissues and homeostatic neuronal processes, including synaptic functions8,9.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Dityatev, A. & Schachner, M. Extracellular matrix molecules and synaptic plasticity. Nat. Rev. Neurosci. 4, 456–468 (2003). source
    • cites [9] Lau, L. W., Cua, R., Keough, M. B., Haylock-Jacobs, S. & Yong, V. W. Pathophysiology of the brain extracellular matrix: a new target for remyelination. Nat. Rev. Neurosci. 14, 722–729 (2013). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

    Premisecitation

    MMP14 is associated with dementia in middle-aged adults in a human cohort with 10,981 participants.

    “Notably, a recent study has revealed that MMP14 is associated with dementia in middle-aged adults in a human cohort with 10,981 participants.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.

    “These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Neuroinflammation can directly damage neurons, impair synaptic plasticity, and disrupt neuronal networks, leading to cognitive decline and functional impairments.

    “Neuroinflammation can directly damage neurons, impair synaptic plasticity, and disrupt neuronal networks, leading to cognitive decline and functional impairments5–7.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Hedden, T. & Gabrieli, J. D. Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5, 87–96 (2004). source
    • cites [6] Mattson, M. P. & Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7, 278–294 (2006). source
    • cites [7] Bishop, N. A., Lu, T. & Yankner, B. A. Neural mechanisms of ageing and cognitive decline. Nature 464, 529–535 (2010). source

      A check is scheduled.

  • Probably not a substantial claim.

    Premisecitation

    MMPs have been implicated in regulating synaptic remodeling and maintaining the blood‒brain barrier (BBB) by altering ECM components.

    “Although MMPs have been implicated in regulating synaptic remodeling and maintaining the blood‒brain barrier (BBB) by altering ECM components11,12, little is known about the effects of MMPs in the context of cognitive aging.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Ethell, I. M. & Ethell, D. W. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J. Neurosci. Res. 85, 2813–2823 (2007). source
    • cites [12] Huntley, G. W. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat. Rev. Neurosci. 13, 743–757 (2012). source

  • It may state two separate claims as one.

    Interpretationown data

    MT1-MMP does not alter BBB integrity in aging and the cognitive rescue conferred by MT1-MMP depletion in ageing is not related to the prevention of BBB disruption.

    “suggesting that MT1-MMP does not alter BBB integrity in aging and that the cognitive rescue conferred by MT1-MMP depletion in ageing is not related to the prevention of BBB disruption.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    MT1-MMP is a key regulator of energy homeostasis and a series of proteolytic events mediated by MT1-MMP contribute to the pathogenesis of multiple age-associated metabolic disorders, including obesity, diabetes, and atherosclerosis.

    “Our recent findings, along with those of other studies, demonstrate that MT1-MMP is a key regulator of energy homeostasis and that a series of proteolytic events mediated by MT1-MMP contribute to the pathogenesis of multiple age-associated metabolic disorders, including obesity, diabetes, and atherosclerosis15–17.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). source
    • cites [16] Guo, X. et al. Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2. Nat. Commun. 13, 7907 (2022). source
    • cites [17] Guo, X. et al. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat. Commun. 13, 3749 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Physiologically, MMP14 cleaves a wide range of substrates, ranging from ECM to growth factor receptors, in a tissue-specific and contextual manner.

    “Physiologically, MMP14 cleaves a wide range of substrates, ranging from ECM to growth factor receptors, in a tissue-specific and contextual manner13,14.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Asthana, P. & Wong, H. L. X. Preventing obesity, insulin resistance and type 2 diabetes by targeting MT1-MMP. Biochim. Biophys. Acta Mol. Basis Dis. 1870, 167081 (2024). source
    • cites [14] Castro-Castro, A. et al. Cellular and molecular mechanisms of MT1-MMP-dependent cancer cell invasion. Annu Rev. Cell Dev. Biol. 32, 555–576 (2016). source

  • It may state two separate claims as one.

    Interpretationown data

    A systemic reduction in MT1-MMP in aged mice can prevent the decline of memory, learning, and synaptic plasticity without significantly altering age-related neuroinflammation.

    “Thus, a systemic reduction in MT1-MMP in aged mice can prevent the decline of memory, learning, and synaptic plasticity without significantly altering age-related neuroinflammation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    MT1-MMP is constitutively shed via proteolytic cleavage by ADAM family metalloproteinases, resulting in detectable quantities of soluble MT1-MMP (sMT1-MMP) in the plasma.

    “MT1-MMP is constitutively shed via proteolytic cleavage by A Disintegrin and Metalloproteinase (ADAM) family metalloproteinases, resulting in detectable quantities of soluble MT1-MMP (sMT1-MMP) in the plasma20–22.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [20] Toth, M. et al. Complex pattern of membrane type 1 matrix metalloproteinase shedding. Regulation by autocatalytic cells surface inactivation of active enzyme. J. Biol. Chem. 277, 26340–26350 (2002). source
    • cites [21] Maisi, P. et al. Soluble membrane-type 1 matrix metalloproteinase (MT1-MMP) and gelatinase A (MMP-2) in induced sputum and bronchoalveolar lavage fluid of human bronchial asthma and bronchiectasis. APMIS 110, 771–782 (2002). source
    • cites [22] Li, H. et al. Immunological characterization of cell-surface and soluble forms of membrane type 1 matrix metalloproteinase in human breast cancer cells and in fibroblasts. Mol. Carcinog. 22, 84–94 (1998). source

  • It may state two separate claims as one.

    Premisecitation

    MT1-MMP/MMP14 increases with age and regulates energy homeostasis.

    “Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Mice showing persistent immobility or unusually high freezing behavior during training were excluded from final analyses.

    “Mice showing persistent immobility or unusually high freezing behavior during training were excluded from final analyses.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    MT1-MMP inhibition may specifically target the pathophysiology of aging and metabolic disorders without affecting normal development.

    “This indicates that MT1-MMP inhibition may specifically target the pathophysiology of aging and metabolic disorders without affecting normal development.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Mice with partial deficiencies in both OCN and GPR158 (Ocn+/−Gpr158+/−) exhibit age-related cognitive impairment, whereas mice with a partial deficiency in either Ocn or Gpr158 alone do not display such cognitive deficits.

    “These observations are further supported by genetic evidence showing that mice with partial deficiencies in both OCN and GPR158 (Ocn+/−Gpr158+/−) exhibit age-related cognitive impairment, whereas mice with a partial deficiency in either Ocn (Ocn+/−) or Gpr158 (Gpr158+/−) alone do not display such cognitive deficits37–39.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [37] Khrimian, L. et al. Gpr158 mediates osteocalcin’s regulation of cognition. J. Exp. Med. 214, 2859–2873 (2017). source
    • cites [38] Kosmidis, S. et al. RbAp48 protein is a critical component of GPR158/OCN signaling and ameliorates age-related memory loss. Cell Rep. 25, 959–973.e956 (2018). source
    • cites [39] Shan, C. et al. Osteocalcin ameliorates cognitive dysfunctions in a mouse model of Alzheimer’s Disease by reducing amyloid beta burden and upregulating glycolysis in neuroglia. Cell Death Discov. 9, 46 (2023). source

  • It may state two separate claims as one.

    Premisecitation

    Exposure to pro-aging circulating factors present in the blood of aged mice induces neuroinflammation and triggers age-related cognitive decline in young rodents.

    “Exposure to pro-aging circulating factors present in the blood of aged mice induces neuroinflammation and triggers age-related cognitive decline in young rodents27,28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Villeda, S. A. et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477, 90–94 (2011). source
    • cites [28] Villeda, S. A. et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat. Med. 20, 659–663 (2014). source

  • It may state two separate claims as one.

    Interpretationown data

    MT1-MMP blockade can rejuvenate the aging brain by restoring hippocampal function and plasticity, independent of other risk factors associated with cognitive aging.

    “In this study, we demonstrated that MT1-MMP blockade can rejuvenate the aging brain by restoring hippocampal function and plasticity, independent of other risk factors associated with cognitive aging.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Cognitive decline associated with aging or metabolic disorders can be reversed by inhibiting MT1-MMP.

    “Our findings suggest that cognitive decline associated with aging/metabolic disorders can be reversed by inhibiting MT1-MMP.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Systemic inhibition of MT1-MMP or specific deletion of MT1-MMP in GFRAL+ brainstem neurons confers protections against diet-induced obesity in mice.

    “Systemic inhibition of MT1-MMP or specific deletion of MT1-MMP in GFRAL+ brainstem neurons confers protections against diet-induced obesity in mice15,17.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). source
    • cites [17] Guo, X. et al. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat. Commun. 13, 3749 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All procedures were approved by the Department of Health under Hong Kong legislation.

    “All the procedures were approved by the Department of Health under Hong Kong legislation.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Blocking MT1-MMP can restore hippocampal function and plasticity in aged mice, maintaining homeostasis seen in young mice.

    “Second, blocking MT1-MMP can restore hippocampal function and plasticity in aged mice, maintaining homeostasis seen in young mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    MMPs, especially MMP9, may contribute to cognitive impairment in neurodegenerative diseases through their involvement in blood-brain barrier (BBB) disruption.

    “Growing evidence has shown that MMPs, especially MMP9, may contribute to cognitive impairment in neurodegenerative diseases through their involvement in blood-brain barrier (BBB) disruption30, a major driving factor for cognitive aging.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Rempe, R. G., Hartz, A. M. S. & Bauer, B. Matrix metalloproteinases in the brain and blood-brain barrier: versatile breakers and makers. J. Cereb. Blood Flow. Metab. 36, 1481–1507 (2016). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Mice that failed to leave the center of the platform within 60 s or that remained immobile and did not explore the maze were excluded from analysis.

    “Mice that failed to leave the center of the platform within 60 s or that remained immobile and did not explore the maze were excluded from analysis55.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Sunyer, B., Patil, S., Höger, H. & Lubec, G. Barnes maze, a useful task to assess spatial reference memory in the mice. Protocol. Exchange 390 (2007). source

  • It may state two separate claims as one.

    Interpretationreasoning

    Aging results in a decrease in OCN bioavailability and an MT1-MMP-mediated reduction in GPR158 expression, both of which contribute to impaired OCN/GPR158 signaling and consequently age-related cognitive decline.

    “Aging results in a decrease in OCN bioavailability and an MT1-MMP-mediated reduction in GPR158 expression, both of which contribute to impaired OCN/GPR158 signaling and consequently, age-related cognitive decline.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Activation of MT1-MMP alone can trigger memory decline and hippocampal plasticity deficits, independent of neuroinflammation and blood-brain barrier disruption.

    “First, we revealed a fundamental vulnerability of the brain, in which activation of MT1-MMP alone can trigger memory decline and hippocampal plasticity deficits, independent of neuroinflammation and blood-brain barrier disruption.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Cognitive integrity is specifically regulated by MT1-MMP, but not by other MMPs that have been implicated in pathological neurodegenerative diseases.

    “Cognitive integrity is specifically regulated by MT1-MMP, but not by other MMPs that have been implicated in pathological neurodegenerative diseases.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    C52 is a brain-penetrant inhibitor of prostaglandin/E2 signaling that suppresses neuroinflammation and restores cognitive function during aging.

    “compound 52 (C52), a brain-penetrant inhibitor of prostaglandin/E2 signaling that suppresses neuroinflammation and restores cognitive function during aging23.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Minhas, P. S. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590, 122–128 (2021). source

  • It may state two separate claims as one.

    Premisecitation

    Genetic ablation or pharmacological inhibition of MT1-MMP confers protection against multiple age-associated disorders, including cognitive decline, obesity, and diabetes, without adverse effects.

    “In fact, our previous studies, along with the current findings, demonstrate that genetic ablation or pharmacological inhibition of MT1-MMP confers protection against multiple age-associated disorders, including cognitive decline, obesity, and diabetes, without adverse effects15–17.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Chow, C. F. W. et al. Body weight regulation via MT1-MMP-mediated cleavage of GFRAL. Nat. Metab. 4, 203–212 (2022). source
    • cites [16] Guo, X. et al. Control of SARS-CoV-2 infection by MT1-MMP-mediated shedding of ACE2. Nat. Commun. 13, 7907 (2022). source
    • cites [17] Guo, X. et al. Regulation of age-associated insulin resistance by MT1-MMP-mediated cleavage of insulin receptor. Nat. Commun. 13, 3749 (2022). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    In the open field test, mice that remained immobile for more than 50% of the session or failed to leave the starting position were excluded from analysis.

    “Mice that remained immobile for an extended period (e.g., more than 50% of the session) or failed to leave the starting position were excluded from analysis57.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Seibenhener, M. L. & Wooten, M. C. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J. Vis. Exp 6, e52434 (2015).

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Interpretationown data

    MT1-MMP, which is activated with aging, cleaves GPR158 to suppress the ability of OCN to promote cognition, thereby leading to a decline in memory function and learning capacity during aging.

    “Together, these results demonstrate that MT1-MMP, which is activated with aging, cleaves GPR158 to suppress the ability of OCN to promote cognition, thereby leading to a decline in memory function and learning capacity during aging.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: MT1-MMP is activated with aging.

  • It may state two separate claims as one.

    Premisecitation

    Ro 28-2653 is an orally available, brain-penetrant inhibitor with high specificity for MT1-MMP, MMP2, and MMP9.

    “Ro 28-2653 is an orally available, brain-penetrant inhibitor with high specificity for MT1-MMP, MMP2, and MMP9.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [31] Abramjuk, C. et al. Matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine: tumor-reducing effects on hormone-sensitive prostate cancer in rats. Anticancer Drugs 16, 855–861 (2005). source
    • cites [32] Genter, M. B., Warner, B. M., Krell, H. W. & Bolon, B. Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653. Toxicol. Pathol. 33, 593–599 (2005). source
    • cites [33] Kilian, M. et al. Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer. Prostaglandins Leukot. Ess. Fat. Acids 75, 429–434 (2006). source
    • cites [34] Lorenzl, S. et al. The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenicALS mice. Exp. Neurol 200, 166–171 (2006). source
    • cites [35] Fisher, J. F. & Mobashery, S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev. 25, 115–136 (2006). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    Mice that accumulated less than 10 s of total exploration time across both objects during the training session were excluded from subsequent analyses.

    “Mice that accumulated less than 10 s of total exploration time across both objects during the training session were excluded from subsequent analyses53.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Vogel-Ciernia, A. & Wood, M. A. Examining object location and object recognition memory in mice. Curr. Protoc. Neurosci. 69, 8 31 31–17 (2014). source

  • It may state two separate claims as one.

    Premisecitation

    Obesity is associated with systemic inflammation, leading to neuroinflammation and cognitive impairment.

    “Obesity is associated with systemic inflammation, leading to neuroinflammation and cognitive impairment29.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Cope, E. C. et al. Microglia Play an Active Role in Obesity-Associated Cognitive Decline. J. Neurosci. 38, 8889–8904 (2018). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    As a hydroxamic acid-based MMP inhibitor, Ro 28-2653 may also display lower binding affinity for other MMPs, as well as for ADAM and ADAMTS metalloproteinases.

    “As a hydroxamic acid-based MMP inhibitor, it may also display lower binding affinity for other MMPs, as well as for ADAM and A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTS) metalloproteinases31–35.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [31] Abramjuk, C. et al. Matrix metalloproteinase inhibitor Ro 28-2653 in combination with estramustine: tumor-reducing effects on hormone-sensitive prostate cancer in rats. Anticancer Drugs 16, 855–861 (2005). source
    • cites [32] Genter, M. B., Warner, B. M., Krell, H. W. & Bolon, B. Reduction of alachlor-induced olfactory mucosal neoplasms by the matrix metalloproteinase inhibitor Ro 28-2653. Toxicol. Pathol. 33, 593–599 (2005). source
    • cites [33] Kilian, M. et al. Matrix metalloproteinase inhibitor RO 28-2653 decreases liver metastasis by reduction of MMP-2 and MMP-9 concentration in BOP-induced ductal pancreatic cancer in Syrian Hamsters: inhibition of matrix metalloproteinases in pancreatic cancer. Prostaglandins Leukot. Ess. Fat. Acids 75, 429–434 (2006). source
    • cites [34] Lorenzl, S. et al. The matrix metalloproteinases inhibitor Ro 28-2653 [correction of Ro 26-2853] extends survival in transgenicALS mice. Exp. Neurol 200, 166–171 (2006). source
    • cites [35] Fisher, J. F. & Mobashery, S. Recent advances in MMP inhibitor design. Cancer Metastasis Rev. 25, 115–136 (2006). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    In electrophysiology, ACSF was saturated with carbogen (95% O2/5% CO2) to maintain oxygenation.

    “ACSF was saturated with carbogen (95% O2/5% CO2) to maintain oxygenation.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    In statistical analyses, the statistical significance was set at P < 0.05.

    “the statistical significance was set at P < 0.05.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    In the nesting test, mice for which nesting scoring was not possible due to observer error were excluded from analysis.

    “Mice for which nesting scoring was not possible due to observer error were excluded from the analysis59.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [59] Deacon, R. Assessing burrowing, nest construction, and hoarding in mice. J. Vis. Exp 5, e2607 (2012). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    In intrahippocampal injections, the needle was left in place for 5 min to minimize the risk of backflow or leakage.

    “the needle was left in place for 5 min to minimize the risk of backflow or leakage.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    After each Y-maze trial, the maze was wiped with 75% ethanol to avoid odor cues.

    “After each trial, the Y-maze was wiped with 75% ethanol to avoid odor cues.”
    Quote in the paperNot a substantial claim

  • 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 given

    In RNA extraction and gene expression analysis, the relative fold-change of each gene was calculated using the 2-ΔΔCt method, and Gapdh was used for normalization.

    “The relative fold-change of each gene was calculated using the 2–ΔΔCt method, and Gapdh was used for normalization.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    In gait analysis, mice displaying refusal to walk, frequent stopping, or excessive grooming or rearing during the test walk were not included in the final analysis.

    “Mice displaying refusal to walk, frequent stopping, or excessive grooming or rearing behaviors during the test walk were not included in the final analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    In the open field test, the box was cleaned with 70% ethanol and dried before the next mouse was placed.

    “The box was cleaned with 70% ethanol and dried before the next mouse was placed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    In the Y-maze test, if a mouse remained immobile or failed to explore all three arms, it was excluded from the study.

    “If a mouse remained immobile or failed to explore all three arms, it was excluded from the study61.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Hughes, R. N. The value of spontaneous alternation behavior (SAB) as a test of retention in pharmacological investigations of memory. Neurosci. Biobehav. Rev. 28, 497–505 (2004). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The Human Protein Atlas (HPA) integrates GTEx transcriptomic data across diverse human tissues.

    “The HPA integrates GTEx transcriptomic data across diverse human tissues.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    In the Morris water maze test, mice exhibiting immobility, passive floating, or a lack of active swimming during trial sessions were not included in the final analysis.

    “Mice exhibiting immobility, passive floating, or a lack of active swimming during the trial sessions were not included in the final analysis63.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [63] Vorhees, C. V. & Williams, M. T. Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat. Protoc. 1, 848–858 (2006). source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductcitation

    In the wire hang test, mice that failed to grasp the wire mesh at the start after three attempts were excluded from analysis.

    “Mice that failed to grasp the wire mesh at the start of the test after three attempts were excluded from the analysis58.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Brooks, S. P. & Dunnett, S. B. Tests to assess motor phenotype in mice: a user’s guide. Nat. Rev. Neurosci. 10, 519–529 (2009). source
70 of 70

  • The authors state this as an assumption.

    It remains unclear how aging and obesity interact to affect cognitive function across the lifespan and how brain function mediates their relationship with cognition.

    “Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact together to affect cognitive function across the life span and how brain function might mediate their relationship on cognition.”

  • The authors state this as an assumption.

    The central inflammatory mediator that links neuroinflammation to cognitive impairment remains undefined.

    “Given the multiple functions of many inflammatory factors, the central inflammatory meditator that links neuroinflammation to cognitive impairment remains undefined.”

  • The authors state this as an assumption.

    The molecular mechanism by which neuroinflammation drives cognitive dysfunctions is largely unclear.

    “The molecular mechanism by which neuroinflammation drives cognitive dysfunctions is also largely unclear.”

  • The authors state this as an assumption.

    Little is known about the effects of MMPs in the context of cognitive aging.

    “little is known about the effects of MMPs in the context of cognitive aging.”

  • The paper relies on this without support.

    MT1-MMP is a major activator of other MMPs, including MMP2 and MMP9.

    “MT1-MMP is a major activator of other MMPs, including MMP2 and MMP9.”

  • The paper relies on this without support.

    MT1-MMP is activated with aging.

    “Together, these results demonstrate that MT1-MMP, which is activated with aging, cleaves GPR158 to suppress the ability of OCN to promote cognition, thereby leading to a decline in memory function and learning capacity during aging.”

  • The paper relies on this without support.

    C52 suppresses neuroinflammation.

    “we administered the neuroinflammation suppressor C52 over two weeks in 18-month-old aged mice, which led to significant improvements in several functional outcomes.”

  • The paper relies on this without support.

    Obesity induces activation of MT1-MMP.

    “These results demonstrate that obesity-indued activation of MT1-MMP suppresses the ability of OCN/GPR158 signaling to promote cognition and that MT1-MMP depletion sensitizes obese mice to the cognition-promoting effect of OCN.”

  • The paper relies on this without support.

    The underlying molecular mechanism of OCN/GPR158 dysregulation in age-related memory loss remains largely unknown.

    “The underlying molecular mechanism of this dysregulation remains largely unknown.”
9 of 9

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.

  • Aged mice in Fig. 4 are assigned conflicting ages

    Major

    The Fig. 4 caption calls the treated mice 18 months old, but the Results and treatment protocol say dosing began at 20 months of age.

  • Plasma-infusion experiment conflicts with blood-transfusion method

    Major

    The Results describe infusing aged or young plasma, but the corresponding method describes administering aged blood or saline. Both the administered material and the control differ.

  • OCN-signaling experiment identifies different Mmp14 genotypes

    Minor

    The Results describe the neurons tested for OCN-induced IP3 accumulation as Mmp14−/−, whereas the Fig. 6 legend identifies them as Mmp14+/−.

  • MMP14 activity has conflicting measurement readouts

    Minor

    The Fig. 1 legend reports the activity measurement in relative fluorescence units, while the assay method says absorbance was recorded at 405 nm and used to calculate concentration.

  • Nesting scale is called five-point but defines six scores

    Minor

    The method calls this a 5-point scale, yet defines scores from 0 through 5, which comprises six distinct scores.

5 of 5

Citations

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Metadata

Authors
Asthana, P., Li, L., Lu, L., Wu, J., Zhang, S., Li, N., Wong, S. K. K., Gurung, S., Zhang, Y., Lin, Y., Peng, Y., Xu, Z., Chan, K. M., Zhai, L., Lyu, A., Bian, Z.-X., Ge, X., Iyaswamy, A., Li, M., Su, Y., Zhou, Z., Xu, P., & Wong, H. L. X.
Affiliations
  • Hong Kong Baptist University (HK)
  • Huanghe Science and Technology College (CN)
  • First Affiliated Hospital Zhejiang University (CN)
  • Sun Yat-sen University (CN)
  • University of Hong Kong (HK)
  • First Affiliated Hospital of Guangzhou Medical University (CN)
  • City University of Hong Kong (HK)
  • The University of Texas Health Science Center at Houston (US)
Corresponding author
  • Asthana, Pallavi
  • Li, Liguo
  • Xu, Pingyi
  • Wong, Hoi Leong Xavier
ORCID
Venue
Cell Discovery
Publisher
Springer Science and Business Media LLC
Published
2025-09-23
Volume
11
Issue
1
Pages
76-76
ISSN
2056-5968 (ISSN-L)
DOI
10.1038/s41421-025-00825-w
PMC
PMC12454644
OpenAlex
W4414445677
Semantic Scholar
4c03761c74d6e1f2447ebd08bbf2a61e6de25c9b
Cited by
4
References
67
Citations by year
2026: 4
FWCI
1.44
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Discovery (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • CityU Scholars (submittedVersion, cc-by)
Funders
  • Research Grants Council, University Grants Committee (12102020)
  • Food and Health Bureau of the Government of the Hong Kong Special Administrative Region | Health and Medical Research Fund (08793626)
  • Innovation and Technology Commission (ITS/058/22MS)
  • National Science Foundation of China | National Natural Science Foundation of China-Yunnan Joint Fund (32322091)
  • Guangzhou Science, Technology and Innovation Commission (2025A03J4482)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
MT1-MMP, MMP-14, obesity, brain aging, cognitive decline, neuroinflammation, hippocampus, synaptic plasticity, GPR158, osteocalcin, learning and memory, neurodegeneration, energy homeostasis

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review