Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures

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

A relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma.

“a relationship between Aβ production and epileptiform activity was established in the APP/PS1 transgenic mouse model as early as 4 months of age, prior to Aβ plaque deposits forming in the brain parenchyma [9, 10].”

• cites [9] Born HA, Kim JY, Savjani RR, Das P, Dabaghian YA, Guo Q, et al. Genetic suppression of transgenic APP rescues hypersynchronous network activity in a mouse model of Alzeimer’s disease. J Neurosci. 2014;34(11):3826–40. sourceDisputed

  The section ‘Overproduction of Aβ is not sufficient to generate EEG abnormalities in double knock-in APP/PS1 mice’ reports no EEG abnormalities in APP/PS1 mice despite elevated Aβ production; these mice were tested at 23–24 months, not 4 months. The paper reports early epileptiform activity in a different model, APP/TTA, by 3 months, and its Discussion argues that Aβ is not the primary cause of those discharges. Page numbers are not available in our copy. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites [10] Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007;55(5):697–711. sourceNot checked — no full text of the source

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

Levels of pTau are not high in the APP/PS1 mouse model.

“Levels of pTau are not high in the APP/PS1 mouse model [36]”

• cites [36] Porquet D, Andrés-Benito P, Griñán-Ferré C, Camins A, Ferrer I, Canudas AM, et al. Amyloid and tau pathology of familial Alzheimer’s disease APP/PS1 mouse model in a senescence phenotype background (SAMP8). Age. 2015;37(1):12. sourceDisputed

  The Results (Characterization in tau pathology; Fig. 9, page unavailable) report higher phospho-tau levels in APP/PS1 mice than in SAMP8 mice at the oldest age tested. The Discussion specifies higher phosphorylation at three tau sites at 12 months, although it found no clear strain differences at earlier ages. The unqualified claim that pTau levels are not high in APP/PS1 mice conflicts with the reported finding at 12 months. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

Loss of excitatory currents due to mutations in NaV1.1 (Scn1a) in Dravet Syndrome results in epilepsy.

“For example, loss of excitatory currents due to mutations in NaV1.1 (Scn1a) in Dravet Syndrome results in epilepsy.”

• cites [38] Catterall WA. Dravet syndrome: a sodium channel interneuronopathy. Curr Opin Physiol. 2018;2:42–50. sourceDisputed

  The Abstract attributes Dravet syndrome to loss of sodium currents and firing in GABAergic inhibitory interneurons, not to loss of excitatory currents. The Mouse Genetic Models section says excitatory neurotransmission increases in response to reduced inhibition. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

miR-155 can set the magnitude and timing of the pro-inflammatory response by targeting the 3'UTR of mRNAs that encode specific anti-inflammatory mediators.

“miR-155 can set the magnitude and timing of the pro-inflammatory response by targeting the 3’UTR of mRNAs that encode specific anti-inflammatory mediators [18, 19].”

• cites [18] Li X, Kong D, Chen H, Liu S, Hu H, Wu T, et al. miR-155 acts as an anti-inflammatory factor in atherosclerosis-associated foam cell formation by repressing calcium-regulated heat stable protein 1. Sci Rep. 2016;6(1):21789. sourcePartly supported

  The Abstract says miR-155 can promote atherosclerosis by relieving BCL6-mediated inhibition of CCL2, and describes 3′-UTR binding as the general mechanism of miRNAs. But the paper does not show that targeting anti-inflammatory mediators sets the magnitude or timing of a pro-inflammatory response. Its Results instead demonstrate miR-155 binding the CARHSP1 3′-UTR and suppressing TNF-α secretion in foam cells. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [19] Mahesh G, Biswas R. MicroRNA-155: a master regulator of inflammation. J Interferon Cytokine Res. 2019;39(6):321–30. sourceSupported

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

In transgenic mice expressing human APP, high levels of Aβ peptide lead to depletion of hippocampal stem cells and impairments in spatial discrimination.

“leading to depletion of hippocampal stem cells and impairments in spatial discrimination [7, 8]”

• cites [7] Fu CH, Iascone DM, Petrof I, Hazra A, Zhang X, Pyfer MS, et al. Early seizure activity accelerates depletion of hippocampal neural stem cells and impairs spatial discrimination in an Alzheimer’s disease model. Cell Rep. 2019;27(13):3741-3751.e4. sourcePartly supported

  The Results sections on NSC pool depletion and spatial discrimination (pages not provided) report fewer hippocampal neural stem cells and impaired spatial discrimination in APP mice relative to controls. They do not establish that high Aβ levels caused those outcomes; the Results on levetiracetam instead implicate early seizure activity in stem-cell depletion. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [8] Sciaccaluga M, Megaro A, Bellomo G, Ruffolo G, Romoli M, Palma E, et al. An unbalanced synaptic transmission: cause or consequence of the amyloid oligomers neurotoxicity? Int J Mol Sci. 2021;22(11):5991. sourcePartly supported

  Section 4 (page unavailable) links Aβ pathology in APP-transgenic mice to synaptic dysfunction and reports hippocampal-dependent memory and behavioral deficits. It does not report depletion of hippocampal stem cells or specifically identify impaired spatial discrimination; searches for those terms and for neurogenesis found no supporting passage. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Tfeb regulates expression of lysosome biogenesis genes.

“This transcription factor regulates expression of lysosome biogenesis genes [31].”

• cites [31] Settembre C, Di Malta C, Polito VA, Arencibia MG, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332(6036):1429–33. sourceSupported

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

Mice overexpressing miR-155 develop chronic-inflammatory states and hematopoietic malignancies.

“mice overexpressing miR-155 develop chronic-inflammatory states and hematopoietic malignancies [23].”

• cites [23] O’Connell RM, Rao DS, Chaudhuri AA, Boldin MP, Taganov KD, Nicoll J, et al. Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder. J Exp Med. 2008;205(3):585–94. sourcePartly supported

  The Results and Discussion report abnormal myeloid proliferation in mice with sustained miR-155 expression, including a myeloproliferative disorder with preleukemic features. The Discussion does not report that these mice developed chronic inflammation or frank hematopoietic malignancy; it explicitly says no frank myeloid leukemia was observed within two months. Page numbers are not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

The endosome/lysosome system is involved in microglia-mediated degradation of internalized Aβ.

“The endosome/lysosome system is involved in microglia-mediated degradation of internalized Aβ [32, 33]”

• cites [32] Majumdar A, Cruz D, Asamoah N, Buxbaum A, Sohar I, Lobel P, et al. Activation of microglia acidifies lysosomes and leads to degradation of Alzheimer amyloid fibrils. Mol Biol Cell. 2007;18(4):1490–6. sourceSupported
• cites [33] Solé-Domènech S, Cruz DL, Capetillo-Zarate E, Maxfield FR. The endocytic pathway in microglia during health, aging and Alzheimer’s disease. Ageing Res Rev. 2016;32:89–103. sourceSupported

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

miRNAs influence the timing and amplitude of innate immune responses.

“As powerful epigenetic modulators of gene expression, miRNAs influence the timing and amplitude of the innate immune responses [15].”

• cites [15] Su W, Aloi MS, Garden GA. MicroRNAs mediating CNS inflammation: small regulators with powerful potential. Brain Behav Immun. 2016;52:1–8. sourceSupported

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

Multiple genetic risk alleles associated with AD are thought to be active in the endosome/lysosome pathway.

“multiple genetic risk alleles associated with AD are thought to be active in this pathway [34].”

• cites [34] Van Acker ZP, Bretou M, Annaert W. Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors. Mol Neurodegener. 2019;14(1):20. sourceSupported

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

Progressive deposits of Aβ fibrils into plaques create a positive feedback loop between inflammation and APP processing.

“The progressive deposits of Aβ fibrils into plaques create a positive feedback loop between inflammation and APP processing [13].”

• cites [13] Röhr D, Boon BDC, Schuler M, Kremer K, Hoozemans JJM, Bouwman FH, et al. Label-free vibrational imaging of different Aβ plaque types in Alzheimer’s disease reveals sequential events in plaque development. Acta Neuropathol Commun. 2020;8(1):222. sourcePartly supported

  The Introduction (page unavailable) says Aβ aggregation induces an inflammatory response and that microglia-driven inflammation is considered to contribute to continued amyloid-fibril build-up. The Abstract and Discussion (pages unavailable) describe increasing fibrillation during plaque development. But the paper does not say that inflammation feeds back into APP processing, so it does not support the full proposed loop. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Expression of miR-155 is required for normal immune function.

“Expression of miR-155 is, therefore, required for normal immune function [24].”

• cites [24] Rodriguez A, Vigorito E, Clare S, Warren MV, Couttet P, Soond DR, et al. Requirement of bic/microRNA-155 for normal immune function. Science. 2007;316(5824):608–11. sourceSupported

May combine two claims.

Patients with EOFAD have an 87-fold increased incidence of seizures relative to the age-matched population, compared to a threefold increase in seizure incidence in LOAD individuals.

“Patients with EOFAD have an 87-fold increased incidence of seizures relative to the age-matched population compared to a threefold increase in seizure incidence in LOAD individuals [6].”

• cites [6] Palop JJ. Epilepsy and cognitive impairments in Alzheimer disease. Arch Neurol. 2009;66(4):435. sourcePartly supported

  The “High Levels of Aβ Cause Epilepsy and Cognitive Deficits” section (page not supplied) reports an 87-fold relative risk of unprovoked seizures for dementia onset at ages 50–59 and a threefold risk for onset at ages 70–79. The claim applies those figures to all early-onset familial AD (EOFAD) and late-onset AD (LOAD), respectively, but the passage defines the groups by age at onset, not by those broader categories. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

In transgenic mice expressing human APP, high levels of Aβ peptide are sufficient to induce epileptiform activity and seizures even in the early stages of the disease process.

“studies using transgenic mice expressing human APP have shown that high levels of Aβ peptide are sufficient to induce epileptiform activity and seizures even in the early stages of the disease process”

• cites [7] Fu CH, Iascone DM, Petrof I, Hazra A, Zhang X, Pyfer MS, et al. Early seizure activity accelerates depletion of hippocampal neural stem cells and impairs spatial discrimination in an Alzheimer’s disease model. Cell Rep. 2019;27(13):3741-3751.e4. sourcePartly supported

  The Results section reports epileptiform spikes in APP mice by 1 month of age and robust seizures by 2 months, supporting the early-activity part of the claim. It does not establish that high Aβ peptide levels are sufficient to cause either outcome; the study examines mice expressing mutant human APP, not Aβ sufficiency. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [8] Sciaccaluga M, Megaro A, Bellomo G, Ruffolo G, Romoli M, Palma E, et al. An unbalanced synaptic transmission: cause or consequence of the amyloid oligomers neurotoxicity? Int J Mol Sci. 2021;22(11):5991. sourceSupported

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

Senescence and inflammatory expression profiles are increased with age and are brain region- and sex-specific.

“Since senescence and inflammatory expression profiles are increase with age and are brain region- and sex-specific [53]”

• cites [53] Zhang X, Pearsall VM, Carver CM, Atkinson EJ, Clarkson BDS, Grund EM, et al. Rejuvenation of the aged brain immune cell landscape in mice through p16-positive senescent cell clearance. Nat Commun. 2022;13(1):5671. sourceSupported

May combine two claims.

Inducible loss of miR-155 in primary microglia in vitro increased catabolism of Aβ1-42, while overexpression of miR-155 significantly reduced catabolism.

“We observed that inducible loss of miR-155 in primary microglia in vitro resulted in increased catabolism of Aβ1–42 while overexpression of miR-155 led significantly reduced catabolism [28].”

• cites [28] Aloi MS, Prater KE, Sopher B, Davidson S, Jayadev S, Garden GA. The pro-inflammatory microRNA miR -155 influences fibrillar β-Amyloid 1–42 catabolism by microglia. Glia. 2021;69(7):1736–48. sourceSupported

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

In ALS mice, germ-line knock-out of miR-155 altered microglia polarization in vivo.

“In ALS (B6/SJL-SOD1G93A transgenic) mice it has been shown that germ-line knock-out of miR-155 altered microglia polarization in vivo [46].”

• cites [46] Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice: role of miR-155 in ALS. Ann Neurol. 2015;77(1):75–99. sourcePartly supported

  The Results section (page unavailable) reports that genetic deletion of miR-155 in SOD1G93A mice reduced pro-inflammatory gene expression in spinal microglia and restored M1 and M0 marker patterns in vivo. However, the Animals section says the knockout mice were produced by crossing B6-congenic SOD1G93A mice with miR-155-deficient mice; it does not identify the knockout cohort as B6/SJL-SOD1G93A mice. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Genetic mouse models of Dravet Syndrome demonstrate that NaV1.1 loss predominantly impacts inhibitory circuitry leading to hyperexcitability.

“genetic mouse models of Dravet Syndrome demonstrate that NaV1.1 loss predominantly impacts inhibitory circuitry leading to hyperexcitability [38].”

• cites [38] Catterall WA. Dravet syndrome: a sodium channel interneuronopathy. Curr Opin Physiol. 2018;2:42–50. sourceSupported

May combine two claims.

Increased levels of miR-155 promotes pro-inflammatory cytokine secretion by targeting SOCS1 message for degradation and downregulating anti-inflammatory cytokines that act via JAK/STAT pathway and NF-kB signaling.

“Increased levels of miR-155 promotes pro-inflammatory cytokine secretion by targeting the Suppressor of Cytokine Signaling 1 (SOCS1) message for degradation and downregulating anti-inflammatory cytokines that act via the JAK/STAT pathway [27, 47] and NF-kB signaling [48].”

• cites [27] Yao R, Ma YL, Liang W, Li HH, Ma ZJ, Yu X, et al. MicroRNA-155 modulates Treg and Th17 cells differentiation and Th17 cell function by targeting SOCS1. PLoS ONE. 2012;7(10):e46082. sourcePartly supported

  The Results report that increased miR-155 lowers SOCS1 protein, increases STAT3/STAT5 phosphorylation, and increases secretion of the pro-inflammatory cytokine IL-17A in activated CD4+ T cells. They do not establish degradation of SOCS1 mRNA, and the Results section on cytokine secretion explicitly reports no significant decrease in the anti-inflammatory cytokines IL-10 or TGF-β1. The NF-κB portion of the citing sentence is attached to a different citation [48]. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [47] Kinjyo I, Hanada T, Inagaki-Ohara K, Mori H, Aki D, Ohishi M, et al. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity. 2002;17(5):583–91. sourceNot checked — no full text of the source
• cites [48] Mann M, Mehta A, Zhao JL, Lee K, Marinov GK, Garcia-Flores Y, et al. An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses. Nat Commun. 2017;8(1):851. sourcePartly supported

  The Results sections on miR-155 overexpression and SHIP1/SOCS1 repression (page unavailable) support the NF-κB portion cited to this paper: elevated miR-155 enhances NF-κB activity, and the paper identifies SHIP1 downregulation as a mechanism. The paper also reports repression of SOCS1, but it does not show that SOCS1-message degradation or downregulation of anti-inflammatory cytokines causes the NF-κB effect; in its experiments, SOCS1 chiefly affected cell proliferation. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Csf1r is required for development, maintenance, and proliferation of microglia.

“The colony stimulating factor 1 receptor (Csf1r) is required for the development, maintenance, and proliferation of microglia”

• cites [51] Oosterhof N, Kuil LE, van der Linde HC, Burm SM, Berdowski W, van Ijcken WFJ, et al. Colony-stimulating factor 1 receptor (CSF1R) regulates microglia density and distribution, but not microglia differentiation in vivo. Cell Rep. 2018;24(5):1203-1217.e6. sourcePartly supported

  The Introduction (page unavailable) reports that Csf1r loss in mice produces an almost complete absence of microglia and describes a homeostatic role in microglial viability and proliferation. This supports a role in development and maintenance, but “required” for proliferation is too absolute: the Discussion (page unavailable) says that loss of three csf1r alleles did not severely impede microglia’s proliferative response to dying neurons. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

As one of five miRNAs located on chromosome 21 flanking the APP gene, pathological implications of additional copies of miR-155 extend beyond inflammatory regulation and have gained interest in Trisomy-21 and AD pathogenesis.

“As one of the five miRNAs located on chromosome 21 flanking the APP gene, the pathological implications of additional copies of miR-155 extend beyond inflammatory regulation and have gained interest and attention in Trisomy-21 and AD pathogenesis [49, 50].”

• cites [49] Alexandrov PN, Percy ME, Lukiw WJ. Chromosome 21-encoded microRNAs (mRNAs): impact on Down’s syndrome and trisomy-21 linked disease. Cell Mol Neurobiol. 2018;38(3):769–74. sourcePartly supported

  The Introduction identifies miR-155 as one of five chromosome 21 miRNAs clustered in the region that also contains APP, and links increased miR-155 dosage to pathogenic signaling in Down syndrome and Alzheimer’s disease. Its specific account of miR-155 concerns complement factor H and inflammatory neurodegeneration; it does not establish a role for miR-155 in those diseases beyond inflammatory regulation. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [50] Zhao Y, Jaber V, Percy ME, Lukiw WJ. A microRNA cluster (let-7c, miRNA-99a, miRNA-125b, miRNA-155 and miRNA-802) encoded at chr21q21.1-chr21q21.3 and the phenotypic diversity of Down’s syndrome (DS; trisomy 21). 2017;11.Not checked — no full text of the source

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

Dysregulation of CSF1R/IL-34 signaling contributes to changes in density and distribution of microglia populations in mouse brain.

“dysregulation of CSF1R/IL-34 signaling contributes to changes in density and distribution of microglia populations in the mouse brain [51].”

• cites [51] Oosterhof N, Kuil LE, van der Linde HC, Burm SM, Berdowski W, van Ijcken WFJ, et al. Colony-stimulating factor 1 receptor (CSF1R) regulates microglia density and distribution, but not microglia differentiation in vivo. Cell Rep. 2018;24(5):1203-1217.e6. sourcePartly supported

  The Discussion reports reduced microglia density and altered distribution with CSF1R haploinsufficiency in zebrafish and humans. It also notes regional differences in microglia numbers in mutant mice, but says it is unclear whether density falls elsewhere in the mouse brain. The Introduction identifies IL-34 as a CSF1R ligand; the cited findings do not establish that dysregulation of IL-34 signaling causes the stated changes in mice. Page numbers were not provided for these passages. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

Microglia functions in response to amyloid are regulated by miR-155 and contribute to circuitry vulnerability and seizures in AD pathophysiology.

“Therefore, microglia functions in response to amyloid are regulated by miR-155 (e.g., phagocytosis) [28] and contribute to circuitry vulnerability and seizures in AD pathophysiology.”

• cites [28] Aloi MS, Prater KE, Sopher B, Davidson S, Jayadev S, Garden GA. The pro-inflammatory microRNA miR -155 influences fibrillar β-Amyloid 1–42 catabolism by microglia. Glia. 2021;69(7):1736–48. sourceSupported

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

Both cell autonomous and non-cell autonomous mechanisms contribute to epilepsy in AD.

“Recent reports suggest both cell autonomous and non-cell autonomous mechanisms are contributors to epilepsy in AD [7, 10].”

• cites [7] Fu CH, Iascone DM, Petrof I, Hazra A, Zhang X, Pyfer MS, et al. Early seizure activity accelerates depletion of hippocampal neural stem cells and impairs spatial discrimination in an Alzheimer’s disease model. Cell Rep. 2019;27(13):3741-3751.e4. sourceCould not verify

  The Results section on chronic levetiracetam treatment compares cell-autonomous and circuit-level explanations for altered neural stem cell dynamics, not for epilepsy in AD. The Discussion says that whether altered neurogenesis affects epileptogenesis in these APP mice remains to be assessed. Searches for cell-autonomous and non-cell-autonomous mechanisms of seizures found no passage establishing both as contributors to epilepsy in AD; page numbers were not available in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [10] Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron. 2007;55(5):697–711. sourceNot checked — no full text of the source

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

miR-155 levels are increased in tissue from Temporal Lobe Epilepsy (TLE) patients.

“Increased levels of miR-155 are observed in tissue isolated from Temporal Lobe Epilepsy (TLE) patients [58].”

• cites [58] Korotkov A, Broekaart DWM, van Scheppingen J, Anink JJ, Baayen JC, Idema S, et al. Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes. J Neuroinflammation. 2018;15(1):211. sourceSupported

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

miR-155 regulates mTOR levels in TLE patient tissue and mouse models.

“A third study aimed at identifying a mechanism impacted by miR-155 expression, where miR-155 was identified to regulate on mTOR levels in TLE patient tissue and mouse models.”

• cites [61] Duan W, Chen Y, Wang X. MicroRNA-155 contributes to the occurrence of epilepsy through the PI3K/Akt/mTOR signaling pathway. Int J Mol Med [Internet]. 2018. https://doi.org/10.3892/ijmm.2018.3711. sourcePartly supported

  The Results section, “Overexpression of miRNA-155 inhibits mTOR protein expression” (page unavailable), reports that miRNA-155 overexpression suppressed p-mTOR in glutamate-stimulated hT22 cells. The patient results report elevated miRNA-155 expression in temporal lobe epilepsy, not regulation of mTOR in patient tissue. The cited passages do not report an experiment in mouse models. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

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

The 5xFAD mouse model exhibits aberrant cortical excitability and altered theta oscillations.

“Previous reports have also identified aberrant cortical excitability and altered theta oscillations in the 5xFAD mouse model [67].”

• cites [67] Siwek ME, Müller R, Henseler C, Trog A, Lundt A, Wormuth C, et al. Altered theta oscillations and aberrant cortical excitatory activity in the 5XFAD model of Alzheimer’s disease. Neural Plast. 2015;2015:1–17. sourceSupported

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

A role of miR-155 in epileptogenesis has been reported.

“A role of miR-155 in epileptogenesis has been reported.”

• cites [58] Korotkov A, Broekaart DWM, van Scheppingen J, Anink JJ, Baayen JC, Idema S, et al. Increased expression of matrix metalloproteinase 3 can be attenuated by inhibition of microRNA-155 in cultured human astrocytes. J Neuroinflammation. 2018;15(1):211. sourceSupported
• cites [59] Huang LG, Zou J, Lu QC. Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis by activating Sestrin-3. Brain Res. 2018;1689:109–22. sourceNot checked — no full text of the source
• cites [60] Fu H, Cheng Y, Luo H, Rong Z, Li Y, Lu P, et al. Silencing MicroRNA-155 attenuates kainic acid-induced seizure by inhibiting microglia activation. NeuroImmunoModulation. 2019;26(2):67–76. sourceNot checked — no full text of the source

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

In Dravet Syndrome, loss of excitatory to inhibitory synaptic neurotransmission leads to epilepsy.

“This was observed in the pathophysiology of Dravet Syndrome where a loss of excitatory to inhibitory synaptic neurotransmission leads to epilepsy [38, 73].”

• cites [38] Catterall WA. Dravet syndrome: a sodium channel interneuronopathy. Curr Opin Physiol. 2018;2:42–50. sourcePartly supported

  The Mouse Genetic Models section reports reduced inhibitory GABAergic neurotransmission but increased excitatory neurotransmission; the Conclusion says the resulting imbalance leads to epilepsy. The paper therefore supports an excitation–inhibition imbalance as the cause, not a loss of excitatory-to-inhibitory synaptic neurotransmission as stated. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [73] Ding J, Li X, Tian H, Wang L, Guo B, Wang Y, et al. SCN1A mutation—beyond Dravet syndrome: a systematic review and narrative synthesis. Front Neurol. 2021;24(12):743726. sourcePartly supported

  The Dravet Syndrome section (page unavailable) describes Dravet syndrome as an epileptic encephalopathy mainly caused by loss-of-function SCN1A mutations. It does not state that a loss of excitatory-to-inhibitory synaptic neurotransmission leads to the epilepsy, so the proposed mechanism is unsupported by this copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

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

miR-155 expression modulates BDNF and TrkB expression.

“Expression of miR-155 modulated expression of BDNF and TrkB [61]”

• cites [61] Duan W, Chen Y, Wang X. MicroRNA-155 contributes to the occurrence of epilepsy through the PI3K/Akt/mTOR signaling pathway. Int J Mol Med [Internet]. 2018. https://doi.org/10.3892/ijmm.2018.3711. sourceSupported

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

Microglial CD39 and P2Y12 deletion leads to increased neuronal hyperexcitability and seizures.

“Altered purinergic signaling through P2Y12 and CD39, where Microglial CD39 and P2Y12 deletion leads to increased neuronal hyperexcitability and seizures [69, 70].”

• cites [69] Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A, et al. Negative feedback control of neuronal activity by microglia. Nature. 2020;586(7829):417–23. sourcePartly supported

  The paper’s Abstract reports that P2ry12 gene inactivation increased neuronal responses to D1 agonist treatment, while microglia-specific CD39 deletion increased striatal neuronal activity and seizure susceptibility. Extended Data Figure 8 also reports more seizures after CD39 deletion. The claim omits that the reported effects were measured following stimulation in mice, and the passage describes P2ry12 inactivation—not a microglia-specific P2ry12 deletion. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [70] Eyo UB, Peng J, Swiatkowski P, Mukherjee A, Bispo A, Wu LJ. Neuronal hyperactivity recruits microglial processes via neuronal NMDA receptors and microglial P2Y12 receptors after status epilepticus. J Neurosci. 2014;34(32):10528–40. sourcePartly supported

  The section “P2Y12 receptor deficiency worsens acute experimental seizures” reports more severe kainate-induced seizures in P2Y12 knockout mice, supporting the P2Y12-and-seizures part of the claim. Our copy does not report a CD39 deletion experiment or show that either deletion increased neuronal hyperexcitability as a separate outcome. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

In areas with limited plaque pathology, microglial processes encircle synaptic elements more often than plaque-associated processes.

“In addition, in areas with limited plaque pathology, microglial processes encircled synaptic elements more often compared with plaque-associated processes [57].”

• cites [57] El Hajj H, Savage JC, Bisht K, Parent M, Vallières L, Rivest S, et al. Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J Neuroinflammation. 2019;16(1):87. sourceSupported

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

Deletion of IL-18 is associated with lethal Picrotoxin-induced seizures in cerebral amyloidosis mice.

“Deletion of IL-18 is associated with lethal Picrotoxin-induced seizures in cerebral amyloidosis mice [71].”

• cites [71] Tzeng TC, Hasegawa Y, Iguchi R, Cheung A, Caffrey DR, Thatcher EJ, et al. Inflammasome-derived cytokine IL18 suppresses amyloid-induced seizures in Alzheimer-prone mice. Proc Natl Acad Sci. 2018;115(36):9002–7. sourceSupported

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

In AD model mice, microglial cell bodies are larger and display ultrastructural signs of cellular stress, especially near plaques, and these cells are overall less phagocytic.

“Previous studies have shown that cell bodies of microglia in AD model mice were larger and displayed ultrastructural signs of cellular stress, especially those nearby plaques and that these cells were overall less phagocytic [57].”

• cites [57] El Hajj H, Savage JC, Bisht K, Parent M, Vallières L, Rivest S, et al. Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J Neuroinflammation. 2019;16(1):87. sourceSupported

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

Intranasal delivery of an miR-155-5p antagomir alleviated acute seizures by countering hippocampal inflammation in a pentetrazol-induced model.

“while intranasal delivery of an miR-155-5p antagomir alleviated acute seizures by countering hippocampal inflammation in pentetrazol-induced model [62].”

• cites [62] Zhou X, Chen J, Tao H, Cai Y, Huang L, Zhou H, et al. Intranasal delivery of miR-155-5p antagomir alleviates acute seizures likely by inhibiting hippocampal inflammation. Neuropsychiatr Dis Treat. 2020;16:1295–307. sourcePartly supported

  The Results report reduced seizure severity and inflammatory markers after intranasal antagomir delivery in the pentetrazol-induced model. The Discussion and Conclusion say blocking hippocampal inflammation was the likely mechanism, whereas the citing sentence presents that causal explanation without the qualification. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

In 5xFAD mice, layer II/III visual cortex neurons show altered temporal distributions (burstiness) in spontaneous activity before plaque formation.

“More recently, Jubal et al., used two-photon calcium imaging to show an altered temporal distributions (burstiness) in the spontaneous activity of layer II/III visual cortex neurons 5xFAD mice, before plaque formation [68].”

• cites [68] Rosales Jubal E, Schwalm M, dos Santos GM, Schuck F, Reinhardt S, Tose A, et al. Acitretin reverses early functional network degradation in a mouse model of familial Alzheimer’s disease. Sci Rep. 2021;11(1):6649. sourceSupported

May combine two claims.

miR-155 copy number is increased in microglia from APP/PS1± miR-155flx/flx CX3CR1CreER/+ mice that received corn oil and in wild-type mice.

“We observed an increase in miR-155 copy number in APP/PS1± miR-155flx/flx CX3CR1CreER/+ that received corn oil (p = 0.0294) and wild-type mice (Fig. 1D; two-way ANOVA, with Tukey’s post hoc correction for multiple comparisons).”

May combine two claims.

miR-155 regulates novel pathways that lead to increased Aβ catabolism in vivo, excitatory synaptic removal, and early onset of hyperexcitability.

“We identified novel pathways regulated by miR-155 that lead to increased Aβ catabolism in vivo, excitatory synaptic removal, as well as early onset of hyperexcitability.”

May combine two claims.

Deletion of miR-155 substantially ameliorated Aβ pathology but concurrently caused circuitry changes leading to hyperexcitability and seizures.

“This is important since deletion of miR-155 substantially ameliorated Aβ pathology but concurrently caused circuitry changes leading to hyperexcitability and seizures.”

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

No significant differences were observed between APP/PS1 and APP/PS1 mice after miR-155 knock-out in microglia in hippocampal lysates.

“We did not observe significant differences between APP/PS1 and APP/PS1 mice after miR-155 knock-out in microglia in hippocampal lysates (data not shown).”

May combine two claims.

There was no significant increase in microglia VGLUT1 internalization after miR-155 deletion in non-AD controls or in 5xFAD microglia relative to wild type.

“There was no significant increase in microglia VGLUT1 internalization after miR-155 deletion in non-AD controls (p = 0.7733) or in 5xFAD microglia (p > 0.999) relative to wild type.”

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

5xFAD microglia demonstrate increased VGAT synapse internalization compared to wild type microglia, though this difference is not statistically significant post hoc.

“Interestingly, 5xFAD microglia demonstrate increased VGAT synapse internalization compared to wild type microglia, though this difference is not statistically significant post hoc (p = 0.1151 with Tukey’s post hoc).”

May combine two claims.

Interictal spikes were observed and significantly increased as early as 1 week after microglia miR-155 deletion.

“Increased interictal spikes were observed and significantly increased as early as 1 week after microglia miR-155 deletion”

May combine two claims.

Inducible loss of miR-155 in microglia results in early onset epileptogenesis, increased seizure severity, and reduced survival in the APP/PS1 AD model.

“We found that inducible loss of miR-155 in microglia results in early onset epileptogenesis, increased seizure severity, and reduced survival in the APP/PS1 AD model.”

May combine two claims.

Loss of miR-155 specifically in microglia resulted in early onset hyperexcitability, increased seizure frequency and burden, and increased mortality in AD mouse models; this is the first identification of a role for miR-155 in hyperexcitability and epileptogenesis.

“Our study is the first to identify a role in hyperexcitability and epileptogenesis for miR-155, where loss of miR-155 specifically in microglia resulted in early onset hyperexcitability, increased seizure frequency and burden, and increased mortality in AD mouse models.”

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

Accumulation of Aβ fibrils and neuronal debris that further activate receptors (TLRs, TREM2, CX3CR1) may establish a non-resolving, or chronic inflammatory state.

“Accumulation of Aβ fibrils and neuronal debris that further activate receptors (TLRs, TREM2, CX3CR1) may establish a non-resolving, or chronic inflammatory state [14].”

• cites [14] Doig AJ. Positive feedback loops in Alzheimer’s Disease: the Alzheimer’s feedback hypothesis. :12.Not matched

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

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

Inflammatory miRNA profiles are altered in tissue, circulating monocytes and serum of AD patients.

“Several studies demonstrate that inflammatory miRNA profiles are altered in tissue, circulating monocytes and serum of AD patients.”

May combine two claims.

Network instability may precede complex plaque pathology and simpler Aβ species could be responsible for the elevated risk of seizures for AD patients.

“Therefore, network instability may precede complex plaque pathology and simpler Aβ species could be responsible for the elevated risk of seizures for AD patients.”

May combine two claims.

miR-155 is a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

“These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.”

The quote only partly states this claim.

Chronic inflammation may prevent microglia-mediated degradation of Aβ via a pathway involving Tfeb suppression by miR-155.

“a pathway by which chronic inflammation may prevent microglia mediated degradation of Aβ.”

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

Observer was blinded to all animal conditions.

“Observer was blinded to all animal conditions.”

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

A limitation of our study is that we did not quantify differences in microglia population dynamics, either in microglia number or turnover, resulting from miR-155 loss in APP/PS1 brain.

“However, a limitation of our study is that we did not quantify differences in microglia population dynamics, either in microglia number or turnover, resulting from miR-155 loss in the APP/PS1 brain.”

May combine two claims.

miR-155 influences how microglia actively modulate excitatory and inhibitory synaptic balance, contributing to hyperexcitability and seizures in AD.

“Our findings support the hypothesis that miR-155 influences how microglia actively modulate excitatory and inhibitory synaptic balance, contributing to hyperexcitability and seizures in AD.”

May combine two claims.

Increased hyperexcitability, seizure burden, and sudden death prior to onset of histologically detectable plaque pathology in APP/PS1 mice are pathophysiological processes sensitive to mechanisms that converge on miR-155 regulation of microglia function.

“Therefore, increased hyperexcitability, seizure burden, and sudden death prior to the onset of histologically detectable plaque pathology in APP/PS1 mice are pathophysiological processes sensitive to mechanisms that converge on miR-155 regulation of microglia function.”

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

Microglia are capable of internalizing Aβ in the rodent brain.

“Studies using radiolabeled or fluorescent Aβ [54] and direct injection of fibrillar Aβ into rat brains [55] demonstrated the capability of microglia to internalize Aβ in the rodent brain.”

• cites [54] Paresce DM, Ghosh RN, Maxfield FR. Microglial cells internalize aggregates of the Alzheimer’s disease amyloid ␤-protein via a scavenger receptor. 13.Not matched

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

• cites [55] Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O’Hare E, et al. Fibrillar ␤-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS In Vivo. 13.Not matched

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

May combine two claims.

In the context of Aβ, specific miR-155 deletion in microglia leads to increased internalization of excitatory synapses and decreased internalization of inhibitory synapses.

“Thus, in the context of Aβ, specific miR-155 deletion in microglia leads to increased internalization of excitatory synapses and decreased internalization of inhibitory synapses.”

May combine two claims.

Our data suggest that Csf1r expression is suppressed in adult microglia in APP/PS1 brain and is unaltered with miR-155 loss.

“Our data suggest that Csf1r expression is suppressed in adult microglia in the APP/PS1 brain and is unaltered with miR-155 loss.”

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

In APP/PS1 mice, proliferation of microglia was threefold.

“While turnover of microglia under homeostatic conditions in the brain is low, in APP/PS1 mice proliferation of microglia was threefold [52].”

• cites [52] Füger P, Hefendehl JK, Veeraraghavalu K, Wendeln AC, Schlosser C, Obermüller U, et al. Microglia turnover with aging and in an Alzheimer’s model via long-term in vivo single-cell imaging. Nat Neurosci. 2017;20(10):1371–6. sourceNot checked — no full text of the source

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

In AD and AMD mouse models, miRNA-146a and miRNA-155 are progressively upregulated and hypothesized to drive inflammatory neurodegeneration through synaptic stripping.

“In AD and age-related macular degeneration (AMD) mouse models, microRNAs miRNA-146a and miRNA-155 are progressively upregulated and hypothesized to drive inflammatory neurodegeneration through synaptic stripping [72].”

• cites [72] Lukiw WJ, Surjyadipta B, Dua P, Alexandrov PN. Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer’s disease (AD) and in age- related macular degeneration (AMD). Int J Biochem Mol Biol. 2012;3(1):105–16.Not checked — no full text of the source

May combine two claims.

The cellular functions of microglia extend to restructuring of already vulnerable circuitry in the context of amyloidosis in mouse models of AD, and these functions converge on pathways modulated by miR-155.

“Our data fit with previous findings and support the hypothesis that the cellular functions of microglia extend to the restructuring of the already vulnerable circuitry in the context of amyloidosis in mouse models of AD, and that these functions converge on pathways modulated by miR-155.”

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

In a rat model of TLE, antagomir inhibition of miR-155 reduced pathophysiological features of TLE.

“In a rat model of TLE, antagomir administration to inhibit miR-155 epigenetic regulation on target mRNAs led to a reduction in the pathophysiological features of TLE [59].”

• cites [59] Huang LG, Zou J, Lu QC. Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis by activating Sestrin-3. Brain Res. 2018;1689:109–22. sourceNot checked — no full text of the source

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

In a kainic acid-induced seizure model, silencing miR-155 attenuated seizures via a microglia-mediated mechanism.

“A different model of kainic acid induced seizures showed that silencing of miR-155 attenuated seizures via a microglia-mediated mechanism [60].”

• cites [60] Fu H, Cheng Y, Luo H, Rong Z, Li Y, Lu P, et al. Silencing MicroRNA-155 attenuates kainic acid-induced seizure by inhibiting microglia activation. NeuroImmunoModulation. 2019;26(2):67–76. sourceNot checked — no full text of the source

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

The 5xFAD cohort was monitored for a short timeframe post miR-155 deletion, and synaptic internalization analysis employed a limited selection of excitatory and inhibitory markers.

“We monitored the 5xFAD cohort for a short timeframe post miR-155 deletion in microglia, and our analysis of synaptic internalization employed a limited selection of excitatory and inhibitory markers.”

May combine two claims.

APP/PS1 mice have a lower seizure threshold when challenged with chemoconvulsants and higher susceptibility to spontaneous seizures compared to age-matched wild-type mice.

“Moreover, APP/PS1 mice present with a lower seizure threshold when challenged with chemoconvulsants along with a higher susceptibility to spontaneous seizures compared to age-matched wild-type mice [66].”

• cites [66] Reyes-Marin KE, Nuñez A. Seizure susceptibility in the APP/PS1 mouse model of Alzheimer’s disease and relationship with amyloid β plaques. Brain Res. 2017;1677:93–100. sourceNot checked — no full text of the source

May combine two claims.

miR-155 is significant in microglia functions in AD pathophysiology and has a pleiotropic impact on circuitry homeostasis.

“Our study underlines the significance of miR-155 in microglia functions in AD pathophysiology and reveals its pleiotropic impact on circuitry homeostasis.”