Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease

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

Four major morphological classes were identified: arborized, polarized, fibroblast-like, and rounded shapes.

“we identified four major classes, as proposed by Jones et al. [28]: arborized, polarized, fibroblast-like and rounded shapes.”

• cites [28] Jones, 2017, Aberrant IPSC-Derived Human Astrocytes in Alzheimer’s Disease, Cell Death Dis. sourceDisputed

  The Materials and methods section (Fluorescence microscopy and image analysis) explicitly says cells were classified into three categories: fibroblast-like, arborised and polarised. The Results section (Induced astrocytes from FAD and SAD patients display cellular atrophy) uses “rounded” to describe a fibroblast-like cell, not a fourth class. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

miR-124 is associated with neuronal function and APP processing.

“Among these, miR-125b is associated with Tau phosphorylation [30], miR-124 with neuronal function and APP processing [25,31], and miR-21 to the regulation of toxicity mediated by Aβ oligomers, both in vitro and in vivo [32].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourceSupported
• cites [31] Kozuka, 2019, MiR-124 Dosage Regulates Prefrontal Cortex Function by Dopaminergic Modulation, Sci. Rep. sourcePartly supported

  The Introduction and Abstract link miR-124 to neuronal development and prefrontal cortex function. The paper does not establish a role for miR-124 in APP processing; APP appears only in a cited reference on neuronal splicing. Thus it supports the neuronal-function part of the attributed claim, but not the APP-processing part. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

miR-21 was suggested to have both harmful and beneficial effects.

“Despite its nonspecificity [33], miR-21 is considered a versatile regulator in the progression of CNS disorders [34] and was suggested to have both harmful and beneficial effects [35,36,37].”

• cites [35] Feng, 2018, MiR-21 Attenuates Apoptosis-Triggered by Amyloid-β via Modulating PDCD4/ PI3K/AKT/GSK-3β Pathway in SH-SY5Y Cells, Biomed. Pharmacother. sourceNot checked — no full text of the source
• cites [36] Burgos, K., Malenica, I., Metpally, R., Courtright, A., Rakela, B., Beach, T., Shill, H., Adler, C., Sabbagh, M., and Villa, S. (2014). Profiles of Extracellular MiRNA in Cerebrospinal Fluid and Serum from Patients with Alzheimer’s and Parkinson’s Diseases Correlate with Disease Status and Features of Pathology. PLoS ONE, 9. sourceCould not verify

  The Introduction discusses miRNAs generally, and the Discussion passages describe other miRNAs, but neither addresses harmful and beneficial effects of miR-21. Searches for “miR-21” and “miR-21 harmful beneficial effects” found no passage making that point in our copy. (LLM, conf=0.72)

  Experimental — accuracy not yet measured
• cites [37] Giuliani, 2021, Circulating Inflamma-MiRs as Potential Biomarkers of Cognitive Impairment in Patients Affected by Alzheimer’s Disease, Front. Aging Neurosci. sourcePartly supported

  The Discussion describes evidence for a neuroprotective role for miR-21 in the CNS, supporting the beneficial-effects portion. It says miR-21’s role in neuroinflammation remains unclear, but does not suggest that miR-21 has harmful effects; its conflicting reports concern circulating levels in Alzheimer’s patients, not harmful versus beneficial effects. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

miR-21 is associated with regulation of toxicity mediated by Aβ oligomers, both in vitro and in vivo.

“Among these, miR-125b is associated with Tau phosphorylation [30], miR-124 with neuronal function and APP processing [25,31], and miR-21 to the regulation of toxicity mediated by Aβ oligomers, both in vitro and in vivo [32].”

• cites [32] Schonrock, N., Ke, Y.D., Humphreys, D., Staufenbiel, M., Ittner, L.M., Preiss, T., and Götz, J. (2010). Neuronal MicroRNA Deregulation in Response to Alzheimer’s Disease Amyloid-β. PLoS ONE, 5. sourcePartly supported

  The Results section on the APP23 mouse model reports miR-21 down-regulation alongside miRNA changes in Aβ-treated neuronal cultures, supporting an in vivo and in vitro association with Aβ exposure (page unavailable). It does not show that miR-21 regulates Aβ-oligomer-mediated toxicity; the Results section on cultured neurons reports no observed toxicity or cell death under the exposure conditions used. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Aβ42 impairs the function of GLT-1 and GLAST in hippocampal astrocytes.

“while Aβ42 was shown to impair the function of the excitatory amino acid transporter (GLT-1) and the glutamate/aspartate transporter (GLAST) in hippocampal astrocytes [12].”

• cites [12] Scimemi, 2013, Amyloid- 1-42 Slows Clearance of Synaptically Released Glutamate by Mislocalizing Astrocytic GLT-1, J. Neurosci. sourcePartly supported

  The Results (page not provided) show that Aβ1–42 reduced GLT-1 surface expression and slowed clearance of synaptically released glutamate. They do not show impaired GLAST function: GLAST surface expression was unchanged after treatment. The claim is supported for GLT-1, but not for GLAST. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

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

miR-124 was upregulated in exosomes from iNEU-PSEN cells.

“Particularly, miR-124 and miR-21 were found to be elevated in exosomes from SWE cells, and miR-124 was upregulated in those from iNEU-PSEN cells [25].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourceSupported

Classified as probably not a substantial claim. May combine two claims.

miRNAs can be released by cells as free species directly into their secretome or selectively enriched in exosomes (diameter <150 nm) that, when internalized by target cells, affect their biological functions.

“In general, miRNAs can be released by cells as free species directly into their secretome or selectively enriched in small extracellular vesicles (exosomes, diameter size <150 nm) that, when internalized by target cells, affect their biological functions [38,39,40,41].”

• cites [38] Pinto, 2017, Exosomes from NSC-34 Cells Transfected with HSOD1-G93A Are Enriched in Mir-124 and Drive Alterations in Microglia Phenotype, Front. Neurosci. sourcePartly supported

  The Results report miR-124 enrichment in exosomes from mSOD1 cells and describe those exosomes as averaging about 130 nm in diameter. The Results also state that exosomal miRNAs can enter recipient cells and change their function. Our copy does not establish the alternative claim that cells release free miRNAs directly into their secretome, or define all exosomes as smaller than 150 nm. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [39] Fernandes, 2018, Secretome from SH-SY5Y APPSwe Cells Trigger Time-Dependent CHME3 Microglia Activation Phenotypes, Ultimately Leading to MiR-21 Exosome Shuttling, Biochimie sourceNot checked — no full text of the source
• cites [40] Garcia, 2022, Protective Signature of IFNγ-Stimulated Microglia Relies on MiR-124-3p Regulation from the Secretome Released by Mutant APP Swedish Neuronal Cells, Front. Pharmacol. sourcePartly supported

  Results §3.1 reports miR-124 in both exosomes and exosome-free secretome, and Results §3.8 reports that miR-124-loaded exosomes are internalized by microglia and affect their function. However, Methods §2.4 defines the exosomes examined as 50–200 nm, not under 150 nm; the paper also describes exosome-free miRNAs as soluble without establishing that they are free, unbound species. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [41] Barbosa, M., Santos, M., de Sousa, N., Duarte-Silva, S., Vaz, A.R., Salgado, A.J., and Brites, D. (2022). Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for MiR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice. Biomedicines, 10. sourcePartly supported

  The Introduction (page not provided) says miRNAs can be released into the secretome as free species or encapsulated in small extracellular vesicles and internalized by neighbouring cells. The Discussion (page not provided) describes miR-124 carried to recipient microglial cells and altering their behaviour. Our copy does not establish selective enrichment in exosomes or the stated diameter of <150 nm. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

miR-21 is nonspecific.

“Despite its nonspecificity [33], miR-21 is considered a versatile regulator in the progression of CNS disorders [34] and was suggested to have both harmful and beneficial effects [35,36,37].”

• cites [33] Jenike, 2021, MiR-21: A Non-specific Biomarker of All Maladies, Biomark. Res. sourceSupported

May combine two claims.

miR-124 and miR-21 were elevated in exosomes from SWE cells.

“Particularly, miR-124 and miR-21 were found to be elevated in exosomes from SWE cells, and miR-124 was upregulated in those from iNEU-PSEN cells [25].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourcePartly supported

  Results §3.1 reports elevated miR-124 in exosomes from SH-SWE cells compared with SH-WT controls. The Discussion (§4) reports miR-21 upregulation in SH-SWE cells, but identifies miR-124 and miR-155—not miR-21—as increased in their exosomes. The claim appears to conflate cellular and exosomal miR-21 levels. (LLM, conf=0.91)

  Experimental — accuracy not yet measured

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

The iPSC lines used were characterized for genetic stability and pluripotency markers.

“Characterization for genetic stability and pluripotency markers of these iPSCs was previously documented in studies using iPSC differentiation into astrocytes and microglia for the screening of AD-associated glial aberrancies [26,27].”

• cites [26] Konttinen, 2019, PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human IPSC-Derived Microglia, Stem Cell Rep. sourcePartly supported

  The Results section (Figure 1B; page unavailable) reports measuring pluripotency markers in iPSCs. Experimental Procedures, “Generation and Maintenance of iPSCs” (page unavailable), says several lines were previously characterized but identifies others as previously uncharacterized. Our copy does not establish that the lines were characterized for genetic stability. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourceSupported

Classified as probably not a substantial claim.

C1q + IL-1α + TNF-α is known to induce neurotoxic reactive astrocytosis.

“known to induce neurotoxic reactive astrocytosis [44]”

• cites [44] Liddelow, 2017, Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia, Nature sourceSupported

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

Astrocytes contribute to neuroinflammation, oxidative stress and calcium imbalance in AD.

“Astrocytes are known to contribute to neuroinflammation, oxidative stress and calcium imbalance in AD [10].”

• cites [10] Preman, P., Alfonso-Triguero, M., Alberdi, E., Verkhratsky, A., and Arranz, A.M. (2021). Astrocytes in Alzheimer’s Disease: Pathological Significance and Molecular Pathways. Cells, 10. sourceSupported

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

miR-21 is considered a versatile regulator in the progression of CNS disorders.

“Despite its nonspecificity [33], miR-21 is considered a versatile regulator in the progression of CNS disorders [34] and was suggested to have both harmful and beneficial effects [35,36,37].”

• cites [34] Bai, 2022, MicroRNA-21 Is a Versatile Regulator and Potential Treatment Target in Central Nervous System Disorders, Front. Mol. Neurosci. sourceSupported

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

In iPSC-derived neurons of FTD and ALS patients, miR-9 is downregulated.

“In iPSC-derived neurons of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients, miRNA(miR)-9 downregulation was found [29]”

• cites [29] Zhang, Z., Almeida, S., Lu, Y., Nishimura, A.L., Peng, L., Sun, D., Wu, B., Karydas, A.M., Tartaglia, M.C., and Fong, J.C. (2013). Downregulation of MicroRNA-9 in IPSC-Derived Neurons of FTD/ALS Patients with TDP-43 Mutations. PLoS ONE, 8. sourcePartly supported

  The Results and Discussion report reduced miR-9 in iPSC-derived patient neurons with TARDBP mutations. The claim omits two limits: the study examined neurons with A90V or M337V mutations, and the reduction in A90V neurons was found only after staurosporine-induced stress, not under untreated conditions. No page number is available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Microglia recognize Aβ oligomers via receptors such as CD36, TLR4, TLR6 and TREM2, acquiring specific AD-associated phenotypes.

“Likewise, microglia, the brain-resident immunocompetent macrophages, also recognize Aβ oligomers via receptors such as CD36, toll-like receptor 4 (TLR4) and TLR6 and triggering receptor expressed on myeloid cells 2 (TREM2), acquiring specific AD-associated phenotypes [14,15,16].”

• cites [14] Heneka, 2015, Neuroinflammation in Alzheimer’s Disease, Lancet Neurol. sourcePartly supported

  The Cellular Players > Microglia section says microglia bind Aβ oligomers through CD36 and TLRs including TLR4 and TLR6, and that Aβ binding through these receptors activates microglia. It also describes diverse microglial phenotypes. But it calls TREM2 an orphan receptor and does not identify it as a receptor for Aβ oligomers. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [15] Bamberger, 2003, A Cell Surface Receptor Complex for Fibrillar β-Amyloid Mediates Microglial Activation, J. Neurosci. sourcePartly supported

  The Introduction and Abstract (page numbers unavailable) identify CD36 as part of a receptor complex involved in microglial activation by fibrillar Aβ, with a proinflammatory response. They do not establish recognition of Aβ oligomers through TLR4, TLR6, or TREM2, or describe specific AD-associated phenotypes. (LLM, conf=0.90)

  Experimental — accuracy not yet measured
• cites [16] Hansen, 2018, Microglia in Alzheimer’s Disease, J. Cell Biol. sourcePartly supported

  The sections on phagocytosis and microglial activation report TREM2-dependent Aβ uptake and AD-associated microglial gene-expression changes. The inflammatory-signaling section says Aβ aggregates or fibrils stimulate Toll-like receptors, but our copy does not identify CD36, TLR4, or TLR6 as receptors for Aβ oligomers, or establish that recognition through this receptor list produces the stated phenotypes. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Microglial miR-21 expression decreases after expression of mutant human SOD1 in N9 murine microglia.

“but also to decrease after the expression of mutant human SOD1 in N9 murine microglia [56].”

• cites [56] Vaz, 2019, Phenotypic Effects of Wild-Type and Mutant SOD1 Expression in N9 Murine Microglia at Steady State, Inflammatory and Immunomodulatory Conditions, Front. Cell. Neurosci. sourceSupported

May combine two claims.

miR-21 is upregulated in differentiated SWE neuroblastoma cells and AD patient iPSC-differentiated neurons.

“Our previous study further confirmed that miR-21 is upregulated in both differentiated SWE neuroblastoma cells and AD patient iPSC-differentiated neurons [25].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourceSupported

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

Microglial miR-21 expression increases after hypoxic treatment and prevents neuronal death.

“Microglial miR-21 expression was shown to increase after hypoxic treatment and to prevent neuronal death [34]”

• cites [34] Bai, 2022, MicroRNA-21 Is a Versatile Regulator and Potential Treatment Target in Central Nervous System Disorders, Front. Mol. Neurosci. sourcePartly supported

  In the ‘miR-21 and Neurodegenerative Diseases’ section (page not provided), the review says microglial miR-21 can protect neurons from cell death under hypoxic conditions. It reports increased miR-21 after hypoxic treatment in mesenchymal stromal cells, not microglia, so it does not support that part of the claim. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

May combine two claims.

iPSC-derived midbrain dopaminergic neurons expressed Tau and MAP-2, as well as pre- and post-synaptic markers.

“iPCS-derived midbrain dopaminergic neurons expressed Tau and microtubule-associated protein 2 (MAP-2), as well as pre- and post-synaptic markers [25].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourceSupported

May combine two claims.

Most AD models support miR-21 upregulation, though expression of miR-21 is not consistent across different AD models.

“Though the expression of miR-21 is not consistent in the different AD models, most of them support its upregulation [34]”

• cites [34] Bai, 2022, MicroRNA-21 Is a Versatile Regulator and Potential Treatment Target in Central Nervous System Disorders, Front. Mol. Neurosci. sourceSupported

May combine two claims.

Differentiated microglia expressed microglial markers and had phagocytic ability.

“Upon differentiation, we obtained microglia revealing markers and phagocytic ability, as reported by Konttinen and colleagues [26] (Figure 4B,C).”

• cites [26] Konttinen, 2019, PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human IPSC-Derived Microglia, Stem Cell Rep. sourceSupported

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

miR-21 is upregulated in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation.

“Our previously published data have shown the upregulation of miR-21 in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation [25,39,40].”

• cites [25] Garcia, G., Pinto, S., Cunha, M., Fernandes, A., Koistinaho, J., and Brites, D. (2021). Neuronal Dynamics and MiRNA Signaling Differ between SH-SY5Y APPSwe and PSEN1 Mutant IPSC-Derived AD Models upon Modulation with MiR-124 Mimic and Inhibitor. Cells, 10. sourceSupported
• cites [39] Fernandes, 2018, Secretome from SH-SY5Y APPSwe Cells Trigger Time-Dependent CHME3 Microglia Activation Phenotypes, Ultimately Leading to MiR-21 Exosome Shuttling, Biochimie sourceNot checked — no full text of the source
• cites [40] Garcia, 2022, Protective Signature of IFNγ-Stimulated Microglia Relies on MiR-124-3p Regulation from the Secretome Released by Mutant APP Swedish Neuronal Cells, Front. Pharmacol. sourceCould not verify

  The Results (section 3.1) report upregulation of miR-124 in SWE cells, not miR-21. The Discussion mentions miR-21 only as a predicted contributor of interest for future study, and the passages found do not report miR-21 levels in PSEN1-mutant iPSC-derived neurons (searched: miR-21, PSEN1 mutation, iPSC-derived neurons). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

Classified as probably not a substantial claim.

Microglial activation is a current condition in AD.

“a current condition in AD [70,71]”

• cites [70] Singh, 2022, Astrocytic and Microglial Cells as the Modulators of Neuroinflammation in Alzheimer’s Disease, J. Neuroinflamm. sourceSupported
• cites [71] Leng, 2021, Neuroinflammation and Microglial Activation in Alzheimer Disease: Where Do We Go from Here?, Nat. Rev. Neurol. sourceNot checked — no full text of the source

May combine two claims.

Sensitization with IL-1α + TNF-α + C1q recapitulates microglial activation and is reported to enhance GFAP protein levels and astrocyte neurotoxicity.

“This sensitization intends to recapitulate that caused by microglial activation, a current condition in AD [70,71], reported to enhance GFAP protein levels and astrocyte neurotoxicity [44].”

• cites [70] Singh, 2022, Astrocytic and Microglial Cells as the Modulators of Neuroinflammation in Alzheimer’s Disease, J. Neuroinflamm. sourcePartly supported

  In “Dysfunctional immune cross-talk cause neuroinflammation” (page unavailable), the review says activated microglia secrete IL-1α, TNF and C1q, inducing neurotoxic A1 astrocytes. “The role of astrocytes in neuroinflammation” (page unavailable) says reactive astrocytes have increased GFAP expression, but does not report that sensitization with this cytokine combination increases GFAP protein levels. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [71] Leng, 2021, Neuroinflammation and Microglial Activation in Alzheimer Disease: Where Do We Go from Here?, Nat. Rev. Neurol. sourceNot checked — no full text of the source
• cites [44] Liddelow, 2017, Neurotoxic Reactive Astrocytes Are Induced by Activated Microglia, Nature sourcePartly supported

  Section 2 reports that IL-1α, TNFα and C1q together mimic the effect of activated-microglia conditioned medium on A1 astrocytes; the Extended Data report neurotoxicity from astrocytes treated with all three. The GFAP passages describe staining and cell morphology, not an increase in GFAP protein levels after that treatment. No page numbers are available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Some authors have stimulated astrocytes with TNF-α and IL-1β to make their pathological profiles more visible.

“some authors have stimulated astrocytes with TNF-α and IL-1β to make their pathological profiles more visible [27].”

• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourceSupported

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

miR-21 targets phosphatase and tensin homolog (PTEN).

“miR-21 was shown to target peroxisome proliferator-activated receptor alpha (PPARα) [73] and phosphatase and tensin homolog (PTEN) [74,75], among others.”

• cites [74] Leroy, 2021, Regulation of PPARα by APP in Alzheimer Disease Affects the Pharmacological Modulation of Synaptic Activity, JCI Insight sourceCould not verify

  In the citing sentence, this source is cited as [73] for miR-21 targeting PPARα; the PTEN claim is attached to [74,75], not this source. The Results and Discussion passages describe APP-mediated regulation of PPARα, but searches for miR-21 and PTEN found no passage linking miR-21 to either target in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [75] Raha, 2021, Activation of PPARα Enhances Astroglial Uptake and Degradation of β-Amyloid, Sci. Signal sourceCould not verify

  The Discussion and Results passages concern PPARα-dependent uptake and degradation of β-amyloid in astrocytes, not miR-21 targeting PTEN. Searches for miR-21, PTEN, and phosphatase and tensin homolog found no passage addressing the claim. In the citing sentence, the PTEN clause is attached to [74,75], rather than the PPARα citation [73]. (LLM, conf=0.76)

  Experimental — accuracy not yet measured

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

Astrocyte hypometabolism is associated with neuronal dysfunction, age, and disease.

“Astrocyte hypometabolism has been described to be associated with neuronal dysfunction, age, and disease [68,69].”

• cites [68] Rocha, 2022, Clozapine Induces Astrocyte-Dependent FDG-PET Hypometabolism, Eur. J. Nucl. Med. Mol. Imaging sourcePartly supported

  The Introduction (page unavailable) links reduced astrocytic glutamate uptake to reduced glucose uptake and discusses whether this could produce FDG-PET hypometabolism like that seen in neurodegenerative disorders. The Discussion (page unavailable) says the authors reproduced a hypometabolic pattern seen in dementia by reducing astrocytic glutamate transport. These passages support a connection to disease-related hypometabolism, but they do not establish an association of astrocyte hypometabolism with age or neuronal dysfunction. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [69] Carter, 2019, Astrocyte Biomarkers in Alzheimer’s Disease, Trends Mol. Med. sourceNot checked — no full text of the source

May combine two claims.

Ast cells displayed heterogeneous shapes, mostly stellate morphology, and expressed GFAP and S100B.

“The cells displayed heterogeneous shapes, but mostly the stellate morphology characteristic of glial cells [27] (Figure 6B), and the astrocyte-associated GFAP and S100B markers (Figure 6C)”

• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourceSupported

May combine two claims.

miR-21 is involved in astrocytic hypertrophy, glial scar progression, and astrocyte reactivity.

“this miRNA was demonstrated to be involved in astrocytic hypertrophy, glial scar progression and astrocyte reactivity [66,67].”

• cites [66] Bhalala, 2012, MicroRNA-21 Regulates Astrocytic Response Following Spinal Cord Injury, J. Neurosci. sourceSupported
• cites [67] Li, 2018, Inhibition of MiR-21 Ameliorates Excessive Astrocyte Activation and Promotes Axon Regeneration Following Optic Nerve Crush, Neuropharmacology sourceNot checked — no full text of the source

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

There are sex-related susceptibilities to developing AD and immune responses.

“According to recent studies, there are sex-related susceptibilities to developing AD and immune responses [65].”

• cites [65] Pomeshchik, 2020, Human IPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies, Stem Cell Rep. sourceCould not verify

  The Results section on quantitative proteomics reports that hippocampal spheroid samples segregated by donor gender and suggests gender-specific comparisons when analyzing disease phenotypes; no page number is available in our copy. That does not establish sex-related susceptibility to developing AD or differences in immune responses. Searches for sex-related AD risk and immune responses found no passage addressing either claim. (LLM, conf=0.72)

  Experimental — accuracy not yet measured

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

HMGB1 dysregulation is implicated in astrocyte dysfunction in the neurodegenerative context.

“a critical alarmin whose dysregulation has been implicated in astrocyte dysfunction in the neurodegenerative context [72]”

• cites [72] Brambilla, 2018, Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis, Front. Neurosci. sourceSupported

Classified as probably not a substantial claim.

Astrocytes contribute to neuroinflammation when reactive.

“because astrocytes are known to contribute to neuroinflammation when reactive”

• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourceSupported

May combine two claims.

Typical cytoskeletal and synaptic proteins and their co-localization were identified in neurons, but no major changes were found between Neu-Ctrl and Neu-AD cells for hallmarks.

“Here, we identified typical cytoskeletal and synaptic proteins (and their co-localization) in neurons, but we did not find major changes between Neu-Ctrl and Neu-AD cells for hallmarks that may derive, at least in part, from their “age resetting” reprogramming process [114].”

• cites [114] Cornacchia, 2017, Back and Forth in Time: Directing Age in IPSC-Derived Lineages, Brain Res. sourceSupported

May combine two claims.

Ast-AD revealed fewer GFAP-positive cells than S100B-positive ones, with low HMGB1 and IL-10 and elevated IL-6 and C/EBPα gene levels.

“Ast-AD revealed fewer GFAP-positive cells than S100B-positive ones, with low HMGB1 and IL-10 and elevated IL-6 and C/EBPα gene levels, already pointing to some altered properties [27,72,120].”

• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourcePartly supported

  The Results section on cytokine secretion (page unavailable) reports higher IL-6 and IL-10 secretion by stimulated PSEN1 ΔE9 astrocytes than controls, supporting altered IL-6 activity but not the claim of low IL-10 or elevated IL-6 gene levels in AD cells. The astrocyte-characterization Results (page unavailable) report GFAP and/or S100β staining, but not fewer GFAP-positive than S100β-positive AD cells. The retrieved passages do not report the claimed HMGB1 or C/EBPα gene levels. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [72] Brambilla, 2018, Dysregulation of Astrocytic HMGB1 Signaling in Amyotrophic Lateral Sclerosis, Front. Neurosci. sourceCould not verify

  The Materials and Methods section describes mouse spinal-cord astrocyte cultures as >99% GFAP-positive, but does not compare GFAP-positive with S100B-positive cells. The Results examine HMGB1 signaling in ALS astrocytes, not the stated Ast-AD profile. Searches for Ast-AD, S100B, IL-10, IL-6, and C/EBPα found no passage addressing that profile; page numbers are unavailable in our copy. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites [120] Gaikwad, 2021, Tau Oligomer Induced HMGB1 Release Contributes to Cellular Senescence and Neuropathology Linked to Alzheimer’s Disease and Frontotemporal Dementia, Cell Rep. sourceCould not verify

  The Results describe GFAP-positive astrocytes in AD and FTD brain tissue and increased HMGB1 and IL-6 in TauO-associated or TauO-stimulated astrocytes. Our copy does not report findings for Ast-AD, compare GFAP-positive with S100B-positive cell counts, or give the claimed IL-10 and C/EBPα gene levels (searched: Ast-AD, S100B, IL-10, C/EBPα). (LLM, conf=0.76)

  Experimental — accuracy not yet measured

May combine two claims.

Generated microglial cells had a typical microglial signature including CD11b, TMEM119, Iba1 and CX3CR1, and demonstrated phagocytic properties.

“Here, we generated microglial cells with the typical microglial signature, including microglia-specific markers (CD11b, TMEM119, Iba1 and CX3CR1), which also demonstrated phagocytic properties, in accordance with similar studies [21,26].”

• cites [21] Abud, 2017, IPSC-Derived Human Microglia-like Cells to Study Neurological Diseases, Neuron sourceSupported
• cites [26] Konttinen, 2019, PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human IPSC-Derived Microglia, Stem Cell Rep. sourceSupported

May combine two claims.

Decreased immunofluorescence and increased gene expression of TREM2 in MG-AD suggest TREM2 imbalance.

“Here, its decreased immunofluorescence and increased gene expression in MG-AD suggest TREM2 imbalance, as Konttinen and colleagues reported for the same cells [26].”

• cites [26] Konttinen, 2019, PSEN1ΔE9, APPswe, and APOE4 Confer Disparate Phenotypes in Human IPSC-Derived Microglia, Stem Cell Rep. sourceCould not verify

  The Results section on iMGL differentiation (page unavailable) reports TREM2 immunostaining as evidence of microglial identity. It does not report decreased TREM2 immunofluorescence, increased TREM2 gene expression, or an imbalance in MG-AD cells. Searches for those terms found no passage addressing the claimed changes. (LLM, conf=0.73)

  Experimental — accuracy not yet measured

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

The continuum of GFAP/S100B-positive cells, ranging from roundish/polarized to highly arborized cells, agrees with previous studies.

“In our study, the continuum of GFAF/S100B-positive cells, ranging from roundish/polarized ones to highly arborized cells, agrees with previous studies [27,28].”

• cites [27] Oksanen, 2017, PSEN1 Mutant IPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer’s Disease, Stem Cell Rep. sourcePartly supported

  The Results section, under “iPSCs Efficiently Differentiate into Functional Astrocytes” (page unavailable), reports GFAP- and/or S100β-positive cells acquiring a stellate morphology. It does not describe the claimed continuum from roundish or polarized to highly arborized cells. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites [28] Jones, 2017, Aberrant IPSC-Derived Human Astrocytes in Alzheimer’s Disease, Cell Death Dis. sourceSupported

May combine two claims.

In AD microglia, miR-21 and miR-146a were upregulated.

“In AD microglia, the upregulation of iNOS and miR-21/miR-146a supports their activation.”

May combine two claims.

AD astrocytes showed high miR-21, low miR-155, and depleted exosomal miRNAs.

“AD astrocytes manifested a restrained inflammatory profile, with high miR-21 but low miR-155 and depleted exosomal miRNAs.”

May combine two claims.

miR-21, miR-124, and miR-125b were upregulated in Neu-AD cells compared with Neu-Ctrl cells (p < 0.05 for all).

“there was a clear upregulation of miR-21, miR-124 and miR-125b (p < 0.05 for all) in Neu-AD cells when compared to Neu-Ctrl cells.”

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

GFAP+ cell number showed a small increase in HC-SWE slices versus controls (p = 0.07, not significant).

“despite the small increase in the number of GFAP+ cells (Figure 2F, p = 0.07)”

May combine two claims.

The cell tracker was stable for 4 DIV but significantly lost fluorescence intensity (p < 0.01, more than 50%) if used for 7 DIV.

“The results showed that while the cell tracker was stable for 4 DIV, it significantly lost fluorescence intensity (p < 0.01, more than 50%) if used for 7 DIV (Figure 1C).”

May combine two claims.

Nearly 45% of microglial cells internalized beads; among those, 23.5% had 1-2, 13.3% had 2-3, and 7.5% had more than 3 beads.

“Nearly 45% of the microglial cells showed internalized beads. Of those, 23.5% presented 1–2 internalized beads, 13.3% presented at least 2–3 beads, and the remaining 7.5% presented more than 3 beads.”

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

Nearly 84% of PSD-95 puncta co-localized with synapsin-1 puncta.

“nearly 84% of the PSD-95 puncta co-localized with synapsin-1 puncta.”

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

Synapsin-1 puncta were more abundant than PSD-95 puncta (3.4 ± 0.7 versus 2.2 ± 0.5).

“synapsin-1 puncta were more abundant than PSD-95 puncta (3.4 ± 0.7 vs. 2.2 ± 0.5, respectively)”

May combine two claims.

Iba1+ cell number and Iba1 fluorescence intensity were higher in HC-SWE slices than in HC-SH slices and non-transplanted slices.

“Stimulation was markedly higher in HC-SWE slices relative to HC-SH slices for Iba1+ cells (p < 0.01) or Iba1 FI (p < 0.05) or as compared with NT slices (p < 0.01) in both conditions (Figure 2C,D).”

May combine two claims.

Relative GFAP fluorescence intensity was markedly higher in HC-SWE slices than in non-transplanted or HC-SH slices (p < 0.01 for both).

“marked differences were obtained in relative GFAP FI as compared with either NT or HC-SH assays (Figure 2G, p < 0.01 for both cases)”

May combine two claims.

Both SH and SWE cells showed more than 80% cell-tracker-positive cells engrafted in the hippocampal margins, though not uniformly distributed.

“with both cell types showing more than 80% cell-tracker-positive cells engrafted in the hippocampal margins (indicated by bold dashed lines), though not uniformly distributed.”

May combine two claims.

Lower expression levels of HMGB1 and IL-10 were found in Ast-AD compared to Ast-Ctrl (p < 0.001 and p < 0.05, respectively).

“we obtained lower expression levels for HMGB1 and IL-10 in Ast-AD as compared to Ast-Ctrl (p < 0.001 and p < 0.05, respectively, Figure 6G).”

May combine two claims.

Immunostimulation led to a decrease in S100B expression in Ast-Ctrl (p < 0.05) but led to its increase in Ast-AD cells (p < 0.05).

“immunostimulation led to a decrease in S100B expression in Ast-Ctrl (p < 0.05) but led to its increase in Ast-AD cells (p < 0.05)”

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

No sex-related differences were found in either AST-Ctrl or AST-AD.

“No sex-related differences were found in either AST-Ctrl or AST-AD (data not shown).”

May combine two claims.

Stressed Ast-AD cells showed a significant increase in fibroblast-like (p < 0.01) and rounded morphological phenotypes (p < 0.05).

“These alterations resulted in a significant increase in fibroblast-like (p < 0.01) and rounded morphological phenotypes (p < 0.05)”

May combine two claims.

Higher expression of C/EBPα (p < 0.05) and IL-6 (p < 0.01) was found in Ast-AD versus Ast-Ctrl cells.

“we found higher expression of the CCAAT/enhancer-binding protein α (C/EBPα) (p < 0.05) and IL-6 (p < 0.01) in Ast-AD vs. Ast-Ctrl cells.”

May combine two claims.

Stressed Ast-AD cells had a major reduction in mean cell perimeter versus respective naïve cells (p < 0.001) and versus stressed Ast-Ctrl cells (p < 0.05).

“causing a major reduction in the mean cell perimeter of stressed Ast-AD (Figure 7I; p < 0.001) vs. respective naïve and vs. stressed Ast-Ctrl cells (p < 0.05).”

May combine two claims.

In WT mouse organotypic cultures transplanted with SWE cells, glial activation and upregulated miR-21 were observed as the first outcomes.

“With WT mouse organotypic cultures transplanted with SWE cells, we attempted to recapitulate the early events leading to neuropathological manifestations caused by AD neuroblastoma cells. Glial activation and upregulated miR-21 were observed as the first outcomes.”

May combine two claims.

CSF miR-21 is elevated in MCI-AD patients but not in MCI-Ctrl individuals.

“Here, despite the low number of samples, we report a clear CSF miR-21 elevation in MCI-AD patients that was not found in MCI-Ctrl individuals.”

May combine two claims.

Ast-AD cells evidenced upregulated miR-21 and downregulated miR-155, and their exosomes were defective in miR-21, miR-124, miR-146a and miR-155.

“The cells also evidenced upregulated miR-21 and downregulated miR-155, and their exosomes were defective in miR-21, miR-124, miR-146a and miR-155.”

May combine two claims.

Stressed astrocytes showed an increased number of fibroblast-like cells and S100B-positive cells, together with dysregulated gene expression and release of sAPPβ and cytokines, indicating a reactive and neurotoxic phenotype.

“These stressed astrocytes showed an increased number of fibroblast-like cells and of S100B-positive cells, together with dysregulated gene expression and the release of sAPPβ and cytokines, indicating their reactive and neurotoxic phenotype.”

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

Underpowered data point to a sex-biased miR-21 expression pattern in Neu-AD cells.

“Despite the underpowered data pointing to a sex-biased miR-21 expression pattern in Neu-AD cells, this is not without precedent since the male-dominant expression of miR-21 is already associated with an increased susceptibility to other diseases [117].”

• cites [117] Hao, 2018, Functional Roles of Sex-Biased, Growth Hormone–Regulated MicroRNAs MiR-1948 and MiR-802 in Young Adult Mouse Liver, Endocrinology sourceNot checked — no full text of the source

May combine two claims.

Other miRNAs characterize each cell type: upregulated miR-146a in microglia, elevated miR-124 and miR-125b in neurons, and downregulated miR-155 in astrocytes.

“This is the case for upregulated miR-146a in microglia, elevated miR-124 and miR-125b in neurons and downregulated miR-155 in astrocytes.”

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

Astrocytes play an important role in Aβ clearance via extracellular protease degradation.

“Despite their susceptibility to Aβ, astrocytes play an important role in its clearance via extracellular protease degradation [13].”

• cites [13] Olabarria, 2010, Concomitant Astroglial Atrophy and Astrogliosis in a Triple Transgenic Animal Model of Alzheimer’s Disease, Glia sourceNot checked — no full text of the source

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

No differences were found between patient cells and matched controls in Ki67 gene expression.

“but no differences were found between patient cells and matched controls when assessed for the gene expression of Ki67, whose protein is widely used as a proliferation marker (data not shown).”

May combine two claims.

miR-21 is a promising biomarker and a disease-modifying target in AD.

“The data from these AD models highlight miR-21 as a promising biomarker and a disease-modifying target to be further explored.”

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

miR-125b is associated with Tau phosphorylation.

“Among these, miR-125b is associated with Tau phosphorylation [30], miR-124 with neuronal function and APP processing [25,31], and miR-21 to the regulation of toxicity mediated by Aβ oligomers, both in vitro and in vivo [32].”

• cites [30] Zhang, 2019, MiR-125b Promotes Tau Phosphorylation by Targeting the Neural Cell Adhesion Molecule in Neuropathological Progression, Neurobiol. Aging sourceNot checked — no full text of the source

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

Melt-curve analysis confirmed specificity of PCR products.

“Melt-curve analysis was performed after amplification, and the specificity of PCR products was confirmed.”

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

Astrocytes evidenced low gene expression of SYP and TREM2.

“Astrocytes evidenced low gene expression of SYP and TREM2 (Supplementary Figure S2).”

May combine two claims.

Microglia-like cells on D24 exhibited phagocytic ability and positive markers TMEM119, Iba1, CX3CR1, MFGE8, Cd11b, TREM2 and Arg-1.

“Cells on D24 exhibited phagocytic ability and several positive markers, such as transmembrane protein 119 (TMEM119), ionized calcium-binding adapter molecule 1 (Iba1), CX3C motif chemokine receptor 1 (CX3CR1), milk fat globule-EGF factor 8 protein (MFGE8), Cd11b, triggering receptor expressed on myeloid cells 2 (TREM2) and Arginase-1 (Arg-1), as documented in the Results section.”

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

Cells were routinely tested for mycoplasma contamination.

“Cells were routinely tested for mycoplasma contamination and cultured in Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and 2% AB/AM (Thermo Fisher Scientific, Waltham, MA, USA) in T75 flasks.”

May combine two claims.

In microglia, SYP and GFAP gene expression was negligible, and Cx43 was scarcely identified.

“In addition, the expression of synaptophysin (SYP) and glial fibrillary acidic protein (GFAP) genes was negligible, and that of connexin 43 (Cx43) scarcely identified (Supplementary Figure S2).”

May combine two claims.

In neurons, SYP expression was predominant compared to astrocytes and microglia, while Cx43, TREM2 and GFAP were scarcely represented.

“When compared to astrocytes and microglia, SYP expression was predominant in neurons, while Cx43, TREM2 and GFAP were scarcely represented (Supplementary Figure S2).”

May combine two claims.

Differentiated iPSC-derived midbrain neurons expressed MAP-2, Tau, synapsin-1, SV-2, PSD-95, and f-actin.

“we observed the typical neuronal cytoskeletal organization using MAP-2 and Tau family proteins, as well as the synaptic markers synapsin-1, SV-2 and PSD-95 (Figure 5B). In addition, we also observed f-actin staining in neurons”

May combine two claims.

MG cells expressed CD11b, TMEM119, Iba1, CX3CR1, and MFGE8.

“We confirmed the ubiquitous expression of CD11b, TMEM119, Iba1 and CX3CR1, together with the MFGE8 protein”

May combine two claims.

Increased miR-21 in SWE cells is secreted into exosomes, leading to CHME3 microglial miR-21 overexpression and inclusion in their derived exosomes.

“Our previous study using human SH/SWE neuroblastoma cells and CHME3 microglia cocultures revealed that increased miR-21 in SWE cells was secreted into their exosomes, which led to CHME3 microglial miR-21 overexpression and its inclusion in their derived exosomes [39].”

• cites [39] Fernandes, 2018, Secretome from SH-SY5Y APPSwe Cells Trigger Time-Dependent CHME3 Microglia Activation Phenotypes, Ultimately Leading to MiR-21 Exosome Shuttling, Biochimie sourceNot checked — no full text of the source

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

Cell tracker dye was confirmed stable during the additional 4 DIV.

“The mixed neuroblastoma–hippocampal slice culture was maintained for an additional 4 DIV, and the cell tracker dye was confirmed to be stable during this period.”

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

Neurons exhibited synapsin-1, SV-2, PSD-95, MAP-2 and Tau.

“Cells also exhibited synapsin-1, synaptic vesicle protein (SV-2), postsynaptic density protein (PSD-95), MAP-2 and Tau, as documented in the Results section.”

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

miR-21 plays an important role in AD neurons by moderating their apoptosis upon Aβ exposure.

“Earlier studies similarly demonstrated that miR-21 plays an important role in AD neurons by moderating their apoptosis upon Aβ exposure [35].”

• cites [35] Feng, 2018, MiR-21 Attenuates Apoptosis-Triggered by Amyloid-β via Modulating PDCD4/ PI3K/AKT/GSK-3β Pathway in SH-SY5Y Cells, Biomed. Pharmacother. sourceNot checked — no full text of the source

May combine two claims.

Microglia display a surveillance role and an alert condition upon pathological SWE cell interaction.

“Data evidence the surveillance role of microglia and the alert condition upon pathological SWE cell interaction.”

May combine two claims.

Exosomal miRNA cargo may depend on intracellular miRNA levels and active/passive transference.

“We have previously shown that exosomal miRNA cargo may depend on intracellular miRNA levels and active/passive transference [39,61,62].”

• cites [39] Fernandes, 2018, Secretome from SH-SY5Y APPSwe Cells Trigger Time-Dependent CHME3 Microglia Activation Phenotypes, Ultimately Leading to MiR-21 Exosome Shuttling, Biochimie sourceNot checked — no full text of the source
• cites [61] Yin, 2020, Neuron-Derived Exosomes with High MiR-21-5p Expression Promoted Polarization of M1 Microglia in Culture, Brain Behav. Immun. sourceNot checked — no full text of the source
• cites [62] Yelamanchili, S.V., Lamberty, B.G., Rennard, D.A., Morsey, B.M., Hochfelder, C.G., Meays, B.M., Levy, E., and Fox, H.S. (2015). MiR-21 in Extracellular Vesicles Leads to Neurotoxicity via TLR7 Signaling in SIV Neurological Disease. PLoS Pathog., 11. sourceNot checked — no full text of the source

May combine two claims.

MCI-AD patients showed positive PiB-PET, low CSF Aβ42, and high CSF levels of total and phospho-Tau.

“Briefly, MCI-AD patients showed positive PiB-PET, low CSF Aβ42 and high CSF levels of total and phospho-Tau (Table 1).”

May combine two claims.

SWE cells, in addition to polarizing astrocytes and microglia, lead to upregulated miR-21 in hippocampal cultures.

“Data highlight that SWE cells, in addition to polarizing astrocytes and microglia, lead to upregulated miR-21 in HCs.”

May combine two claims.

miR-21 (mainly in male patients), miR-124, and miR-155 have the potential to be considered promising biomarkers of neuronal AD pathology in circulating exosomes.

“our data suggest that miR-21 (mainly in male patients), miR-124 and miR-155 have the potential to be considered promising biomarkers of neuronal AD pathology in circulating exosomes.”

May combine two claims.

miR-21 has translatable potential because of its consistent overexpression in different patient samples, multiple disease models and multiple cell types, and its trafficking into exosomes.

“In this study, we identified miR-21 as having translatable potential for its consistent overexpression in different patient samples, multiple disease models and multiple cell types and its trafficking into exosomes.”

May combine two claims.

Ast-AD cells have an over-reactive response relative to Ast-Ctrl cells, with noticeable consequences for the secretome composition.

“This finding indicates the over-reactive response of Ast-AD cells relative to that of Ast-Ctrl cells, with noticeable consequences for the secretome composition.”

May combine two claims.

Microglial cells were active contributors to miR-21 upregulation in the experimental models, but this was not enough to counteract neuroinflammation and several AD-related pathological markers.

“It is noted, however, that even considering that microglial cells were active contributors to miR-21 upregulation in our experimental models, it was not enough to counteract neuroinflammation and several AD-related pathological markers.”

May combine two claims.

Exosomal transfer was verified in exosomes from Neu-AD and immunostimulated Ast-AD cells, supporting miR-21's role in mediating regulatory/pathological functions in AD cells and promoting similar effects on near and distant recipient cells.

“This was verified in those from Neu-AD and from immunostimulated Ast-AD cells, thus supporting miR-21’s emerging role in mediating regulatory/pathological functions in such AD cells, but also in promoting similar effects on near and distant recipient cells.”

May combine two claims.

This study is pioneer in identifying miR-21 upregulation in several tested models of human AD, highlighting its potential relevance as a crucial player in AD pathophysiology.

“This study is thus pioneer in identifying miR-21 upregulation in several tested models of human AD, thus highlighting its potential relevance as a crucial player in AD pathophysiology.”

• AssumptionRests on an assumption: Changes in miRNA profiles in human models of AD have been scarcely investigated, and translation to the regulation of miRNAs as a potential therapy is lacking.

May combine two claims.

Less than 15% SYP expression was detected in astrocyte cultures, whereas neuronal cultures had almost undetectable GFAP expression.

“Less than 15% SYP expression was detected in astrocyte cultures, in contrast to neuronal cultures, where almost undetectable GFAP expression was obtained.”

May combine two claims.

The study highlights the transversal relevance of miR-21 among the selected miRNA hits and validates its potential as a target/biomarker in AD pathophysiology.

“Our study highlights the transversal relevance of miR-21 among our selected set of miRNA hits and validates its potential as a target/biomarker in AD pathophysiology.”

• AssumptionRests on an assumption: At present, there is no effective therapy for AD.

May combine two claims.

Despite criticism of miR-21 as a biomarker, the study provides a multi-model dataset confirming its potential as a therapeutic target to explore in AD.

“In summary, despite the criticism involving miR-21 as a biomarker for most diseases, here, we provide a multi-model dataset confirming its potential as a therapeutic target to explore in AD.”

• AssumptionRests on an assumption: At present, there is no effective therapy for AD.

May combine two claims.

All MCI patients enrolled in the study revealed similar cognitive complaints, with distinctive profiles only in amyloid and neurodegenerative-associated biomarkers.

“It is also emphasized that all MCI patients enrolled in this study revealed similar cognitive complaints, only showing distinctive profiles in amyloid and neurodegenerative-associated biomarkers.”

May combine two claims.

The lack of PPARα changes in Neu-AD may derive from concomitant upregulation of miR-125b, and in non-stressed AST-AD from coexistent miR-155 downregulation.

“The lack of PPARα changes in Neu-AD may derive from the concomitant upregulation of miR-125b and, in the non-stressed AST-AD, from the coexistent miR-155 downregulation condition.”