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Cited by 4Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease

Open access
Wyatt‐Johnson, Season K., Ackley, Samantha, Warren, Jalyn, Priya, Raj, Wan, Jun, Liu, Sheng, Brutkiewicz, Randy R.·2025·Alzheimer's & Dementia
DOI 10.1002/alz.14480PMC PMC11848147
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Abstract

INTRODUCTION: Plaques are a hallmark feature of Alzheimer's disease (AD). We found that the loss of mucosal‐associated invariant T (MAIT) cells and their antigen‐presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models. However, it remains unknown how this axis is impacting dystrophic neurites. METHODS: Brain tissue from 5XFAD mice and those that are MR1 deficient (MR1 KO), were analyzed for dystrophic neurites, amyloid plaques, and synapses via immunofluorescence, RNA sequencing, enzyme‐linked immunosorbent assay, and western blot. RESULTS: In 8‐month‐old 5XFAD/MR1 KO mice, there was reduced expression of lysosomal‐associated membrane protein 1, ubiquitin, and n ‐terminal amyloid precursor protein in the hippocampus compared to 5XFAD mice ( P < 0.05). 5XFAD/MR1 KO mice also had less insoluble amyloid beta 40 ( P < 0.001) and higher levels of postsynaptic density protein 95 ( P < 0.01) in the hippocampus. DISCUSSION: Our data contribute additional mechanistic insight into the detrimental role of the MR1/MAIT cell axis in AD pathology development. Highlights: 5XFAD mice lacking the innate immune MR1/MAIT (mucosal‐associated invariant T) cell axis (5XFAD/MR1 KO) have reduced numbers of dystrophic neurite markers in the hippocampus at 8 months of age. Hippocampal tissue transcriptional analyses showed reduced expression of genes encoding classical dystrophic neurite markers in 5XFAD/MR1 KO mice. 5XFAD/MR1 KO mice had less insoluble amyloid beta 40 and increased levels of the post‐synaptic marker, postsynaptic density protein 95, in the hippocampus than did MR1+ 5XFAD mice.

AI snapshot

Written from the paper’s full text.

TL;DR

In 5XFAD Alzheimer’s disease model mice, loss of the MR1/MAIT cell axis reduced hippocampal dystrophic neurite markers, lowered insoluble Aβ40, and increased postsynaptic PSD95 compared with MR1-sufficient 5XFAD mice. The authors conclude that MR1, more than MAIT cells, contributes to dystrophic neurite development and AD pathology.

Key findings

  • In 8-month-old 5XFAD/MR1 KO versus 5XFAD hippocampus, LAMP1 was reduced (P = 0.0342), ubiquitin was reduced (P = 0.002), and NT-APP was reduced at 6 months (P = 0.0321) and 8 months (P < 0.0001).
  • Single-nuclei RNA sequencing of hippocampus showed decreased expression of *Lamp1*, *APP*, *PSAP*, and *Pld3*, and increased *Mapt*, in 5XFAD/MR1 KO mice; 31 cell clusters were identified.
  • 5XFAD/MR1 KO mice had lower insoluble Aβ40 in hippocampus (P = 0.0006) and cortex (P = 0.0157), lower soluble Aβ42 in hippocampus (P = 0.0386), and higher hippocampal PSD95 than 5XFAD mice (P = 0.0092); synaptophysin did not differ between these groups (P = 0.7984).
  • Primary neurons presented *E. coli* antigens to MAIT cells and induced IL-2 production (F[4,10] = 152.9, P < 0.0001), which was blocked by anti-MR1 antibody (P < 0.0001), indicating functional neuronal MR1.

Methods

  • Male and female 5XFAD and 5XFAD/MR1 KO mice on a C57BL/6 background were analyzed using immunofluorescence, immunohistochemistry, densitometry, single-nuclei RNA sequencing, ELISA, western blot, and neuronal–MAIT cell co-culture.
  • Histology and densitometry compared 6- and 8-month-old mice; ELISA measured soluble and insoluble Aβ40/Aβ42 in hippocampus and cortex from 4-, 6-, and 8-month-old mice; single-nuclei RNA sequencing used hippocampi from one male and one female per genotype.
  • Statistical tests included Student t test, one-way ANOVA with Dunnett multiple comparisons, and two-way ANOVA with Tukey or Šidák multiple comparisons; alpha was 0.05, data are mean ± SEM, and samples were blinded before analysis.

Limitations

  • Stated: the exact mechanism(s) by which MR1 and/or MAIT cells impact dystrophic neurite markers require follow-up; how CD4/CD8 expression changes contribute remains to be determined; and the mechanism by which MR1 regulates LAMP1 is not fully understood.
  • Stated: ELISA could not be restricted to specific subregions, unlike prior immunofluorescence analyses focused on CA1 and temporal cortex; hippocampus included CA1, CA2, CA3, and dentate gyrus, and cortex included all subregions.
  • Evident: findings are from a mouse model only, with no human subjects; several experiments used small group sizes (e.g., n = 3–4/group for histology and n = 4 total for single-nuclei RNA sequencing), which limits generalizability and statistical power.

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

Integrity signals

Registry

Crossref · 10.1002/alz.14480

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

27 of 33 cited sources checked · 16 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    The MR1/MAIT cell axis substantially contributes to AD neuropathology.

    “We have recently reported that an immune axis consisting of the major histocompatibility complex class I‐like molecule MR1 and mucosal‐associated invariant T (MAIT) cells substantially contribute to the neuropathology of AD. 7 , 8”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source
    • cites [8] Wyatt‐Johnson SK, Kersey HN, Brutkiewicz RR. Enrichment of liver MAIT cells in a mouse model of Alzheimer's disease. J Neuroimmunol. 2024; 390: 578332. doi: 10.1016/j.jneuroim.2024.578332 38537322 PMC11382344 source

      The Introduction (page unavailable) reports that loss of MAIT cells delayed amyloid-β accumulation in 5XFAD mice, supporting a role for this axis in a mouse model of AD pathology. The paper does not establish that the axis substantially contributes to AD neuropathology generally; its liver findings concern MAIT-cell abundance and activation, not a causal effect on neuropathology. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    In 5XFAD mice, lack of the MR1/MAIT cell axis results in slower development of AD brain pathology than in mice with the axis.

    “We found that the loss of mucosal‐associated invariant T (MAIT) cells and their antigen‐presenting molecule MR1 caused a delay in plaque pathology development in AD mouse models.”
    • Also stated in: § BACKGROUND · plain
      “In our prior study, we found that the 5XFAD mouse model of AD lacking the MR1/MAIT cell axis developed AD brain pathology significantly slower than those mice with this innate immune axis. 7”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source
  • Premisecitation

    These findings are consistent with previous work indicating that 5XFAD/MR1 KO mice have overall less amyloid pathology than MR1+ 5XFAD mice.

    “Importantly, these findings are consistent with our previous work indicating that 5XFAD/MR1 KO mice have overall less amyloid pathology than MR1+ 5XFAD mice. 7”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source
  • Premisecitation

    CD44 is higher on MAIT cells than conventional T cells in 8-month-old 5XFAD mice throughout the cortex and hippocampus.

    “the latter is higher on MAIT cells than conventional T cells in 8‐month‐old 5XFAD mice 7 throughout the cortex and hippocampus”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source

      The Results (Fig. 5; page not provided) report increased MAIT-cell numbers in the cortex and hippocampal CA1 region of 8-month-old 5XFAD mice. The Fig. 5 caption identifies CD44-positive cells in the MAIT-cell gating strategy, but the paper does not report higher CD44 expression on MAIT cells than on conventional T cells; its comparison with non-MAIT T cells concerns CD69 and CD25. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premiseown data

    Previously, the authors' results showed decreased Aβ, which would negatively correlate with PLD3 expression.

    “Previously, our results showed decreased Aβ, 7 which would negatively correlate with PLD3 expression.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source
  • Classified as probably not a substantial claim. 20
  • May combine two claims. 16

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PSD95 is a critical postsynaptic protein, involved in the plasticity and stabilization of the synapse.

    “PSD95 is a critical postsynaptic protein, involved in the plasticity and stabilization of the synapse. 37”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [37] Horner AE, Norris RH, McLaren‐Jones R, et al. Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2. Genes Brain Behav. 2021; 20(1): e12723. doi: 10.1111/gbb.12723 33347690 PMC7615670 source

      The Introduction describes PSD-95 as a central organiser of postsynaptic protein complexes involved in synaptic plasticity, supporting its critical postsynaptic role. It says PSD-95 anchors a receptor at the membrane, but does not establish that it stabilizes the synapse itself; that part of the claim is unsupported. No page number is available in our copy. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The loss of the MR1/MAIT cell axis is not only delaying amyloid pathology but all the pathology.

    “This is consistent with our previous findings that the loss of the MR1/MAIT cell axis is not only delaying amyloid pathology but all the pathology. 7”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source

      The Abstract Results report that loss of the MR1/MAIT cell axis slowed amyloid-beta plaque pathology in 5XFAD mice. The Discussion says future work is needed to determine its contribution to the entire pathology of Alzheimer’s disease, including tau build-up, so the claim that it delays all pathology is not supported. (LLM, conf=0.92)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The 5XFAD mouse is a model of early-onset AD.

    “notably, the 5XFAD mouse is a model of early‐onset AD. 35”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Wyatt‐Johnson SK, Brutkiewicz RR. The complexity of microglial interactions with innate and adaptive immune cells in Alzheimer's disease. Front Aging Neurosci. 2020; 12: 592359. doi: 10.3389/fnagi.2020.592359 33328972 PMC7718034 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Tau is important in axonal stability.

    “Of note, the Mapt (microtubule‐associated protein tau) gene that encodes tau, which is important in axonal stability, 20 was increased in its expression in 5XFAD/MR1 KO mice (Figure 3B).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [20] Mummery CJ, Borjesson‐Hanson A, Blackburn DJ, et al. Tau‐targeting antisense oligonucleotide MAPT(Rx) in mild Alzheimer's disease: a phase 1b, randomized, placebo‐controlled trial. Nat Med. 2023; 29(6): 1437‐ 1447. doi: 10.1038/s41591-023-02326-3 37095250 PMC10287562 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PLD3 levels are negatively correlated with Aβ and cognitive function.

    “PLD3 levels have been reported to be negatively correlated with Aβ and cognitive function, 21 , 34”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [21] Nackenoff AG, Hohman TJ, Neuner SM, et al. PLD3 is a neuronal lysosomal phospholipase D associated with beta‐amyloid plaques and cognitive function in Alzheimer's disease. PLoS Genet. 2021; 17(4): e1009406. doi: 10.1371/journal.pgen.1009406 33830999 PMC8031396 source

      The Results section reports that higher prefrontal cortex PLD3 expression was associated with lower β-amyloid plaque burden. But it also associates higher PLD3 expression with slower cognitive decline, not poorer cognitive function; the claimed negative correlation with cognitive function reverses that relationship. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites [34] Mabrouk R, Miettinen PO, Tanila H. Most dystrophic neurites in the common 5xFAD Alzheimer mouse model originate from axon terminals. Neurobiol Dis. 2023; 182: 106150. doi: 10.1016/j.nbd.2023.106150 37172911 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pld3 has been shown to be downregulated in the hippocampus of AD patient brains.

    “Expression of another gene, Pld3 (Phospholipase D3), that has been shown to be downregulated in the hippocampus of AD patient brains, 21 was also decreased in 5XFAD/MR1 KO compared to 5XFAD mice.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Nackenoff AG, Hohman TJ, Neuner SM, et al. PLD3 is a neuronal lysosomal phospholipase D associated with beta‐amyloid plaques and cognitive function in Alzheimer's disease. PLoS Genet. 2021; 17(4): e1009406. doi: 10.1371/journal.pgen.1009406 33830999 PMC8031396 source

      The Results report lower PLD3 levels in human AD cases than in cognitively normal participants, but the Methods identify the sampled human tissue as dorsolateral prefrontal cortex. The reported reduction in hippocampal PLD3 mRNA is in AD-BXD mice, not human patients. Although the Fig. 3 caption calls the human measurements hippocampal, that conflicts with the Methods and the surrounding Results, so the claimed human hippocampal finding is not established by this copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PSD95 has protective effects against Aβ-induced synaptic changes.

    “Another study demonstrated that PSD95 has protective effects against Aβ‐induced synaptic changes. 38”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Dore K, Carrico Z, Alfonso S, et al. PSD‐95 protects synapses from beta‐amyloid. Cell Rep. 2021; 35(9): 109194. doi: 10.1016/j.celrep.2021.109194 34077732 PMC8237704 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD4 can be upregulated on microglia during a human immunodeficiency virus infection.

    “it is important to note that CD4 can be upregulated on microglia during an human immunodeficiency virus infection 22 and CD8 has been found on microglia/macrophages after a stroke. 23”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [22] Gumbs SBH, Berdenis van Berlekom, A, Kubler R, et al. Characterization of HIV‐1 infection in microglia‐containing human cerebral organoids. Viruses. 2022; 14(4): 829. doi: 10.3390/v14040829 35458559 PMC9032670 source

      The Results (§3.1; page unavailable) report CD4 expression on microglia, and the Introduction (§1; page unavailable) describes CD4 as a receptor involved in HIV infection of microglia. Neither passage says that HIV infection upregulates CD4; the cited paper supports its presence, not the claimed increase. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    5XFAD mice had reduced integrated density staining of NeuN compared to WT at 6 and 8 months of age in the hippocampus, but not in the cortex.

    “we found reduced integrated density staining of NeuN in our 5XFAD mice compared to WT at 6 and 8 months of age in the hippocampus (Figure S3A in supporting information; 6 months: P = 0.0007; 8 months: P = 0.0121), but not in the cortex (Figure S3B; 6 months: P = 0.7957; 8 months: P = 0.7516).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [27] Eimer WA, Vassar R. Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal Abeta42 accumulation and Caspase‐3 activation. Mol Neurodegener. 2013; 8: 2. doi: 10.1186/1750-1326-8-2 23316765 PMC3552866 source

      The Results section on progressive neuron loss reports neuron loss in 5XFAD mice and a possible onset around 6 months, but it measures cortical Layer 5 neurons by stereology, not hippocampal NeuN integrated density. The paper does not report the cited 6- and 8-month hippocampus-versus-cortex staining comparison or its P values; the citing sentence presents those as its authors’ own findings. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    PLD3 is thought to be a risk gene in late-onset AD, and found alongside other lysosomal markers, such as LAMP2, in human tissue.

    “It is also thought to be a risk gene in late‐onset AD, and found alongside other lysosomal markers, such as LAMP2, in human tissue; 21”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [21] Nackenoff AG, Hohman TJ, Neuner SM, et al. PLD3 is a neuronal lysosomal phospholipase D associated with beta‐amyloid plaques and cognitive function in Alzheimer's disease. PLoS Genet. 2021; 17(4): e1009406. doi: 10.1371/journal.pgen.1009406 33830999 PMC8031396 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    CD8 has been found on microglia/macrophages after a stroke.

    “it is important to note that CD4 can be upregulated on microglia during an human immunodeficiency virus infection 22 and CD8 has been found on microglia/macrophages after a stroke. 23”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [23] Boddaert J, Bielen K, Jongers B, et al. CD8 signaling in microglia/macrophage M1 polarization in a rat model of cerebral ischemia. PLoS One. 2018; 13(1): e0186937. doi: 10.1371/journal.pone.0186937 29342151 PMC5771556 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PSAP is involved in the regulation of lysosomes.

    “Moreover, these data also revealed decreased expression of the genes encoding APP and PSAP (prosaposin), the latter of which is involved in the regulation of lysosomes. 19”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [19] Mendsaikhan A, Tooyama I, Bellier JP, et al. Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer's disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun. 2019; 7(1): 215. doi: 10.1186/s40478-019-0862-8 31864418 PMC6925443 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    It has been suggested that synaptophysin may be reduced before observable PSD95 reductions occur.

    “it has been suggested that synaptophysin may be reduced before observable PSD95 reductions occur. 37 , 38”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [37] Horner AE, Norris RH, McLaren‐Jones R, et al. Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2. Genes Brain Behav. 2021; 20(1): e12723. doi: 10.1111/gbb.12723 33347690 PMC7615670

      Not checked in the free run.

    • cites [38] Dore K, Carrico Z, Alfonso S, et al. PSD‐95 protects synapses from beta‐amyloid. Cell Rep. 2021; 35(9): 109194. doi: 10.1016/j.celrep.2021.109194 34077732 PMC8237704 source

      The Introduction (page unavailable) reports reduced PSD-95 in Alzheimer’s disease tissue and in neural tissue exposed to β-amyloid. The paper does not report that synaptophysin falls before PSD-95; a search for synaptophysin found no relevant passage in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MR1 mostly traffics intracellularly within LAMP1+ late endosomes/lysosomes.

    “Although MR1 mostly traffics intracellularly within LAMP1+ late endosomes/lysosomes, 32 , 33”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Harriff MJ, Karamooz E, Burr A, et al. Endosomal MR1 trafficking plays a key role in presentation of mycobacterium tuberculosis ligands to MAIT cells. PLoS Pathog. 2016; 12(3): e1005524. doi: 10.1371/journal.ppat.1005524 27031111 PMC4816560 source

      The Results section ('MR1 localizes to vesicular compartments with late endosome and lysosome markers'; page not provided) says most observed MR1 was intracellular. It says only subsets of MR1-positive endosomal compartments co-localized with Lamp1 and other late-endosome or lysosome markers, while MR1 was also observed in an ER-like compartment. It therefore does not establish that MR1 is mostly within Lamp1-positive late endosomes or lysosomes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [33] Lamichhane R, Ussher JE. Expression and trafficking of MR1. Immunology. 2017; 151(3): 270‐ 279. doi: 10.1111/imm.12744 28419492 PMC5461101 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MAIT cells contribute to inflammatory conditions in the central nervous system and periphery.

    “MAIT cells are an innate‐like T cell subpopulation that has been found to contribute to inflammatory conditions, both in the central nervous system and periphery. 9 , 10”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] Shrinivasan R, Wyatt‐Johnson SK, Brutkiewicz RR. The MR1/MAIT cell axis in CNS diseases. Brain Behav Immun. 2024; 116: 321‐ 328. doi: 10.1016/j.bbi.2023.12.029 38157945 PMC10842441 source
    • cites [10] Wyatt‐Johnson SK, Afify R, Brutkiewicz RR. The immune system in neurological diseases: what innate‐like T cells have to say. J Allergy Clin Immunol. 2024; 153(4): 913‐ 923. doi: 10.1016/j.jaci.2024.02.003 38365015 PMC10999338 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Dystrophic neurites are often surrounding Aβ plaques.

    “What can also be observed in the close vicinity of (often surrounding) Aβ plaques are neurites with an altered morphology—termed “dystrophic neurites.” 5 , 6”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [5] Kosik KS. The Neuritic Dystrophy of Alzheimer's Disease: Degeneration or Regeneration?. Springer; 1991: 234‐ 240.

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

    • cites [6] Tsering W, Prokop S. Neuritic plaques—Gateways to understanding Alzheimer's disease. Mol Neurobiol. 2024; 61(5): 2808‐ 2821. doi: 10.1007/s12035-023-03736-7 37940777 PMC11043180 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The 5XFAD mice were bred and crossed with MR1 KO mice to generate 5XFAD/MR1 KO mice, which did not alter AD transgene expression in the 5XFAD mice.

    “The 5XFAD mice were bred and crossed with the MR1 KO mice to generate 5XFAD/MR1 KO mice, which did not alter AD transgene expression in the 5XFAD mice. 7”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [7] Wyatt‐Johnson SK, Kersey HN, Codocedo JF, et al. Control of the temporal development of Alzheimer's disease pathology by the MR1/MAIT cell axis. J Neuroinflammation. 2023; 20(1): 78. doi: 10.1186/s12974-023-02761-6 36944969 PMC10029194 source

  • May combine two claims.

    Findingown data

    In synaptophysin protein intensity, there was an overall main effect of genotype (F[3,24] = 8.562, P = 0.00205), with a decrease in 5XFAD compared to WT B6 mice (P = 0.0003).

    “In the levels of synaptophysin protein intensity, there was an overall main effect of genotype (F[3,24] = 8.562, P = 0.00205), with a decrease in the 5XFAD compared to WT B6 mice (P = 0.0003).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neurons were able to present E. coli antigens to MAIT cells and induce their production of IL-2 (F[4,10] = 152.9, P < 0.0001).

    “Importantly, we found that neurons were indeed able to present E. coli antigens to MAIT cells and induce their production of IL‐2 (F[4,10] = 152.9, P < 0.0001).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was an overall change in PSD95 levels (F[3,40] = 5.846, P = 0.0021), with significantly decreased intensity in 5XFAD mice compared to WT mice (P = 0.0026).

    “There was an overall change in PSD95 levels (F[3,40] = 5.846, P = 0.0021), with a significantly decreased intensity in 5XFAD mice compared to WT mice (P = 0.0026).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    Single-nuclei RNA sequencing of hippocampus identified 31 distinct cell clusters, with a majority being neurons.

    “We were able to find 31 distinct clusters of cells, with a majority of the clusters being neurons (Figure 3A; Figure S1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    5XFAD/MR1 KO mice have reduced soluble Aβ42 and a decrease in insoluble Aβ40 and Aβ42 compared to the 5XFAD mice.

    “Notably, 5XFAD/MR1 KO mice have reduced soluble Aβ42 and a decrease in insoluble Aβ40 and Aβ42 compared to the 5XFAD mice.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Older MR1 KO mice, regardless of 5XFAD status, have lower levels of NeuN protein expression.

    “This could also have an impact in explaining why older MR1 KO mice, regardless of 5XFAD status, have lower levels of NeuN protein expression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The intensity of NeuN staining is MR1 dependent, and MR1-deficient mice (with or without the 5XFAD transgenes) have lower NeuN levels.

    “Therefore, this suggests that the intensity of NeuN staining is MR1 dependent, and MR1‐deficient mice (with or without the 5XFAD transgenes) have lower NeuN levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In human AD, the soluble form of Aβ40 shifts to insoluble and this insoluble Aβ40 potentially plays a large role in the progression and/or onset of AD.

    “In human AD, the soluble form of Aβ40 shifts to insoluble and this insoluble Aβ40 potentially plays a large role in the progression and/or onset of AD. 36”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Wang J, Dickson DW, Trojanowski JQ, Lee VM. The levels of soluble versus insoluble brain Abeta distinguish Alzheimer's disease from normal and pathologic aging. Exp Neurol. 1999; 158(2): 328‐ 337. doi: 10.1006/exnr.1999.7085 10415140 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mice lacking various scaffolding or GTPase-activating proteins associated with neurodegenerative disorders, it has been suggested that cognitive performance is worsened with lower PSD95 levels.

    “In line with this idea, in mice lacking various scaffolding or GTPase‐activating proteins that are associated with neurodegenerative disorders, it has been suggested that cognitive performance is worsened with lower PSD95 levels. 37”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Horner AE, Norris RH, McLaren‐Jones R, et al. Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2. Genes Brain Behav. 2021; 20(1): e12723. doi: 10.1111/gbb.12723 33347690 PMC7615670 source

      Checked before — its earlier verdict is held back until a new check runs.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All samples were blinded to the researcher before the start of each analysis.

    “All samples were blinded to the researcher before the start of each analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    This is the first study to show that dystrophic neurites and NeuN staining are decreased and PSD95 levels increased, in an AD mouse model with a deficiency in the MR1/MAIT cell axis.

    “Overall, to our knowledge, this is the first study to show that dystrophic neurites and NeuN staining are decreased and PSD95 levels increased, in an AD mouse model with a deficiency in the MR1/MAIT cell axis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The reduced formation of dystrophic neurites and increased synaptic density marker support the possibility that the MR1/MAIT cell axis is detrimental to Alzheimer's disease.

    “The reduced formation of dystrophic neurites and an increased synaptic density marker support the possibility that the MR1/MAIT (mucosal‐associated invariant T) cell axis is detrimental to Alzheimer's disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    This work adds further mechanistic insight into the role of the MR1/MAIT cell axis in AD pathology development and highlights MR1 as a key component of the axis in dystrophic neurite formation.

    “Thus, this work adds further mechanistic insight into the role of the MR1/MAIT cell axis in AD pathology development and highlights MR1 as a key component of the axis in dystrophic neurite formation.”
    Quote in the paperSubstantial claim
30 of 30

  • The paper relies on this without support.

    The 5XFAD mouse model is a valid model of Alzheimer's disease.

    “5XFAD AD model mice”
    “5XFAD mouse model of AD”

  • The paper relies on this without support.

    MR1 knockout mice are MAIT cell-deficient.

    “Using 5XFAD mice crossed onto an MR1‐ and MAIT cell‐deficient (MR1 KO) background”
2 of 2

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.

  • Discussion reverses the reported cortical insoluble Aβ42 result

    Major

    The discussion says MR1-deficient 5XFAD mice have decreased insoluble Aβ42, but the results report more insoluble Aβ42 in their cortex than in controls.

  • PLD3 and Aβ changes do not show the claimed negative correlation

    Minor

    The paper reports decreased Pld3 expression and decreased Aβ in MR1-deficient mice. Those changes move in the same direction, rather than supporting the claimed negative correlation.

2 of 2

Cites

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Related

Authors
Wyatt‐Johnson, S. K., Ackley, S., Warren, J., Priya, R., Wan, J., Liu, S., & Brutkiewicz, R. R.
Affiliations
Indiana University Indianapolis (US)
Corresponding author
  • Wyatt‐Johnson, Season K.
  • Brutkiewicz, Randy R.
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2025-01-08
Volume
21
Issue
2
Pages
e14480-e14480
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.14480
PMC
PMC11848147
OpenAlex
W4406172713
Cited by
4
References
38
Citations by year
2026: 2 · 2025: 2
FWCI
2.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (R21 AG071269‐01)
  • National Institute of Allergy and Infectious Diseases (T32‐AI‐060519)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, MR1
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Hippocampus, Humans, Mice, Transgenic, Synapses, Histocompatibility Antigens Class I, Amyloid beta-Peptides, Neurites, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Plaque, Amyloid

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-30.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-30.

Cited sources are checked by 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 ›

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