Cholesterol-driven pathological astrocytic responses in diabetes-associated cognitive impairment through astrocytic SCAP accumulation and NF-κB–C3 signaling modulation

Probably not a substantial claim.

Astrocytes play a vital role in cholesterol synthesis and metabolism within the brain.

“Astrocytes, essential for maintaining central nervous system (CNS) homeostasis and defense, play a vital role in cholesterol synthesis and metabolism within the brain28,29.”

• cites [28] Escartin, C. et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci. 24, 312–325 (2021). sourceCould not verify

  The Human stem cells section mentions dysregulated lipid metabolism in disease-derived astrocytes, and From morphology to functional studies discusses other metabolic functions. Neither passage addresses cholesterol synthesis or cholesterol metabolism in the brain; searches for those terms found no supporting passage in our copy. Page numbers were not available. (LLM, conf=0.70)

  Experimental — accuracy not yet measured
• cites [29] Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018). sourcePartly supported

  The ‘Definition and Overview of Function’ section says astrocytes sustain CNS homeostasis and provide defense, supporting the first part of the citing sentence. The passages retrieved for ‘cholesterol’ and astrocyte cholesterol synthesis do not address cholesterol synthesis or metabolism, so the claim’s central cholesterol-specific part is not supported by our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

These astrocyte transformations exacerbate neurodegeneration and reduce the ability of astrocytes to maintain synaptic plasticity.

“These transformations exacerbate neurodegeneration and reduce the ability of astrocytes to maintain synaptic plasticity36–38.”

• cites [36] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). sourcePartly supported

  The Introduction reports that A1 astrocytes contribute to neuronal death after acute CNS injury, while the Concluding Remarks say they could drive neurodegeneration in disease; that broader disease claim remains tentative. The section on decreased synaptic functions reports fewer, weaker synapses and possible failure to maintain them, but does not directly establish reduced synaptic plasticity. Page numbers are unavailable in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [37] Joshi, A. U. et al. Fragmented mitochondria released from microglia trigger A1 astrocytic response and propagate inflammatory neurodegeneration. Nat. Neurosci. 22, 1635–1648 (2019). sourcePartly supported

  The Results section reports that activated astrocytes propagated neuronal damage and cell death, supporting the neurodegeneration part of the claim. Our copy does not report that these transformations reduce astrocytes’ ability to maintain synaptic plasticity (searched: “synaptic plasticity” and “synapse”). Page numbers were not available in the indexed passages. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [38] Lian, H. et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85, 101–115 (2015). sourcePartly supported

  The Results section on astroglial NFκB/C3 activation reports reduced synaptic density and dendritic complexity in neurons exposed to activated astroglia, supporting neuronal harm. But the paper does not show that astrocytes lose the ability to maintain synaptic plasticity; its Discussion instead suggests that C3/C3aR signaling may promote plasticity. The claim also describes the observed neuronal impairment more broadly as exacerbated neurodegeneration. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

HFD/STZ mice exhibited elevated fasting glucose, impaired glucose tolerance, insulin resistance and dyslipidemia with increased serum triglycerides, total cholesterol and LDL-C levels.

“HFD/STZ mice also exhibited elevated fasting glucose (Supplementary Fig. 1b), impaired glucose tolerance, insulin resistance (Supplementary Fig. 1c,d) and dyslipidemia with increased serum triglycerides (TG), total cholesterol and LDL-C levels (Supplementary Fig. 1e–h), indicating metabolic disturbances.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

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

HFD/STZ-induced diabetic mice exhibited significantly increased body weights compared with controls.

“After 4 months of dietary and glycemic manipulation, the HFD/STZ-induced diabetic mice exhibited significantly increased body weights compared with the controls, reflecting an obesogenic effects of HFD/STZ (Supplementary Fig. 1a).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

HFD/STZ group exhibited prolonged escape latency, fewer platform crossings and reduced time in the target quadrant in the MWM, indicating impaired spatial learning and memory.

“Behavioral tests, including MWM, Y-maze and novel object recognition (NOR), demonstrated that the HFD/STZ group exhibited prolonged escape latency (Fig. 1b, c), fewer platform crossings (Fig. 1d) and reduced time in the target quadrant (Fig. 1e) in the MWM, indicating impaired spatial learning and memory, with no differences in swimming velocity (Supplementary Fig. 1i).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

Astrocytic complexity, as indicated by branch length and number, was reduced in Cre-, f/f HFD/STZ mice, but these deficits were restored by astrocyte-specific SCAP deletion.

“Moreover, astrocytic complexity, as indicated by branch length and number, was reduced in Cre-, f/f HFD/STZ mice, but these deficits were restored by the astrocyte-specific SCAP deletion (Fig. 6f–h).”

It may state two separate claims as one.

Elevated SCAP expression in astrocytes of T2DM mice correlated with cognitive dysfunction, impaired synaptic plasticity and altered astrocyte morphology.

“We found elevated SCAP expression in the astrocytes of T2DM mice, correlated with cognitive dysfunction, impaired synaptic plasticity and altered astrocyte morphology.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

HFD/STZ-induced mice showed greater SCAP puncta numbers and fluorescence intensity within astrocytes in DG and CA3 regions than NCD-fed mice, with an increasing trend but no significant changes in CA1.

“HFD/STZ-induced mice showed greater SCAP puncta numbers and fluorescence intensity within astrocytes in DG (**P = 0.0017 and **P = 0.0092) (Fig. 4d, e, (1)) and CA3 (****P < 0.0001 and **P = 0.0085) (Fig. 4d, e, (2)) regions than NCD-fed mice, with an increasing trend but no significant changes in CA1 (Fig. 4d, e, (3)).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.
• AssumptionRests on an assumption: SCAP is predominantly expressed in astrocytes and neurons.

It may state two separate claims as one.

Mean integrated fluorescence intensity of C3 colocalized with GFAP was increased in DG and CA3 regions of hippocampus, whereas there was no significant change in CA1.

“Further analysis showed that the mean integrated fluorescence intensity of C3, which colocalized with GFAP, was increased in the DG (Fig. 2k, (1)) and CA3 (Fig. 2k, (2)) regions of the hippocampus, whereas there was no significant change in the CA1 region (Fig. 2k, (3)).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

Neurons cocultured with SCAP-overexpressing astrocytes showed reduced dendrite length (MAP2) and reduced synaptic density (SYP).

“We then performed an astrocyte–neuron coculture (Supplementary Fig. 7d), and the neuron cocultured with SCAP-overexpressing astrocytes showed reduced dendrite length (MAP2) (Supplementary Fig. 7e) and reduced synaptic density (SYP) (Supplementary Fig. 7f).”

It may state two separate claims as one.

NF-κB inhibitor BAY11-7082 suppressed SCAP-induced C3 activation in primary astrocytes, highlighting the SCAP-NF-κB-C3 pathway's role.

“The NF-κB inhibitor BAY11-7082 suppressed the SCAP-induced C3 activation in primary astrocytes, highlighting the SCAP–NF-κB–C3 pathway’s role (Supplementary Fig. 8j,k).”

It may state two separate claims as one.

Astrocytes in HFD/STZ mice exhibited smaller volumes and areas, larger soma volumes and reduced branch length, branch number and branch endpoints.

“Astrocytes in HFD/STZ mice exhibited smaller volumes (Fig. 3b) and areas (Fig. 3c), larger soma volumes (Fig. 3d) and reduced branch length (Fig. 3e), branch number (Fig. 3f) and branch endpoints (Fig. 3g).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

Immunofluorescence confirmed SCAP colocalization with IκBα in astrocytes, whereas coimmunoprecipitation showed a strong interaction between SCAP and IκBα.

“Immunofluorescence confirmed SCAP colocalization with IκBα in astrocytes (Fig. 9e), whereas coimmunoprecipitation showed a strong interaction between SCAP and IκBα (Fig. 9g).”

It may state two separate claims as one.

Combined high-glucose and LDL-C treatment increased p-IκBα levels, and p-IκBα was found in the Golgi but not the ER.

“Combined high-glucose and LDL-C treatment increased p-IκBα levels (Fig. 9b, c), and p-IκBα was found in the Golgi but not the ER (Fig. 9d).”

It may state two separate claims as one.

CUT&RUN-qPCR confirmed NF-κB binding to C3 genomic regions, with predicted NF-κB binding sites at the C3 promoter region.

“A CUT&RUN–Quantitative Real-time polymerase chain reaction (qRT-PCR) confirmed NF-κB binding to C3 genomic regions, with predicted NF-κB binding sites at the C3 promoter region (Fig. 8g–i).”

It may state two separate claims as one.

SCAP elevation activates NF-κB by recruiting IκBα to the Golgi apparatus, promoting C3 transcription.

“SCAP elevation activates NF-κB by recruiting IκBα to the Golgi apparatus, promoting C3 transcription.”

• AssumptionRests on an assumption: SCAP is predominantly expressed in astrocytes and neurons.

It may state two separate claims as one.

C3aRA treatment significantly increased total dendritic length of WTA neurons compared with DMSO, mimicking enhanced dendritic complexity observed in KOA cocultures; no further increase was observed with C3aRA treatment in KOA cocultures.

“The quantitative analysis confirmed that C3aRA treatment significantly increased the total dendritic length of WTA neurons compared with DMSO (Fig. 7k; P < 0.05), mimicking the enhanced dendritic complexity observed in KOA cocultures; no further increase was observed with C3aRA treatment in KOA cocultures.”

It may state two separate claims as one.

Astrocyte-specific SCAP KO resulted in specific SCAP inhibition in astrocytes, with no changes in SCAP expression in neurons or other tissues.

“Immunohistochemistry and reverse-transcription polymerase chain reaction confirmed specific SCAP inhibition in astrocytes (Fig. 5a), with no changes in SCAP expression in neurons (Supplementary Fig. 4e) or other tissues (Supplementary Fig. 4f).”

It may state two separate claims as one.

Among 202 patients with T2DM, 76 were diagnosed with MCI, whereas 126 exhibited normal cognitive function.

“Among these individuals, 76 were diagnosed with MCI, whereas 126 exhibited normal cognitive function.”

It may state two separate claims as one.

Phosphorylated NF-κB levels increased significantly in astrocytes treated with 25 mM glucose and 100 μg/ml LDL-C, although neither treatment alone had this effect.

“The phosphorylated NF-κB levels increased significantly in astrocytes treated with 25 mM glucose and 100 μg/ml LDL-C, although neither treatment alone had this effect (Fig. 8b, c).”

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

The MCI group was older, had fewer years of education and included a higher proportion of females than the non-MCI group.

“The MCI group was older, had fewer years of education and included a higher proportion of females (Table 1).”

It may state two separate claims as one.

Sholl analysis showed decreased intersections with Sholl spheres in Cre-, f/f HFD/STZ mice, which were alleviated in AS cKO HFD/STZ mice.

“A Sholl analysis of pyramidal neurons showed decreased intersections with Sholl spheres in Cre-, f/f HFD/STZ mice, which were alleviated in AS cKO HFD/STZ mice (Supplementary Fig. 5h).”

It may state two separate claims as one.

HFD/STZ-induced astrocytes exhibited smaller volumes and areas in the CA3 and DG regions, which were ameliorated in AS cKO mice.

“The quantitative analysis of astrocyte morphology using Imaris software showed that HFD/STZ-induced astrocytes exhibited smaller volumes and areas in the CA3 (Fig. 6c–e) and DG regions (Supplementary Fig. 6f–h), which were ameliorated in AS cKO mice.”

It may state two separate claims as one.

Dendrite length and synaptic density of neurons cocultured with SCAP-rescued astrocytes were reduced, accompanied by a decrease in level of synaptic proteins (PSD95 and GAP43).

“Meanwhile, the dendrite length and synaptic density of neurons cocultured with SCAP-rescued astrocytes were reduced (Supplementary Fig. 7k–m), accompanied by a decrease in the level of synaptic proteins (PSD95 and GAP43) (Supplementary Fig. 7n).”

It may state two separate claims as one.

Cholesterol accumulation was observed in DACI-model mice and correlated with impaired learning and memory.

“Consistent with studies linking abnormal cholesterol metabolism to cognitive decline in DM14,15, we observed cholesterol accumulation in DACI-model mice, which correlated with impaired learning and memory.”

• cites [14] Zhang, H. et al. Inverted U-shaped correlation between serum low-density lipoprotein cholesterol levels and cognitive functions of patients with type 2 diabetes mellitus. Lipids Health Dis. 20, 103 (2021). sourceCheck pending
• cites [15] Shi, J. et al. Increased plasma level of 24S-hydroxycholesterol and polymorphism of CYP46A1 SNP (rs754203) are associated with mild cognitive impairment in patients with type 2 diabetes. Front. Aging Neurosci. 13, 619916 (2021). sourceCheck pending

It may state two separate claims as one.

The MCI group demonstrated lower cognitive test scores and significantly higher serum C3 levels than controls.

“The MCI group demonstrated lower cognitive test scores (Supplementary Fig. 10a) and significantly higher serum C3 levels than controls (P = 0.016; Supplementary Fig. 10b).”

It may state two separate claims as one.

SCAP overexpression and rescue experiments mediated increased NF-κB transcriptional activity, also shown by increased binding to the C3 locus.

“In addition, SCAP overexpression and rescue experiments mediated increased NF-κB transcriptional activity, also shown by the increased binding to the C3 locus (Supplementary Fig. 8b,d).”

It may state two separate claims as one.

No differences in body weight, fasting blood glucose, glucose tolerance or lipid metabolism were detected between Cre-, HFD/STZ and AS cKO HFD/STZ groups.

“No differences in body weight (Supplementary Fig. 5a), fasting blood glucose (Supplementary Fig. 5b), glucose tolerance (Supplementary Fig. 5c) and lipid metabolism were detected between Cre-, HFD/STZ and AS cKO HFD/STZ groups (Supplementary Fig. 5d–g).”

It may state two separate claims as one.

Combined high-glucose and LDL-C treatment enhanced NF-κB nuclear translocation and upregulated C3 mRNA expression.

“The combined treatment also enhanced NF-κB nuclear translocation (Fig. 8d, e) and upregulated C3 mRNA expression (Fig. 8f).”

It may state two separate claims as one.

HFD/STZ-induced mice exhibited elevated p-NF-κB levels compared with NCD-fed mice, which were reduced after astrocyte SCAP deletion.

“HFD/STZ-induced mice exhibited elevated phosphorylated-NF-kappaB (p-NF-κB) levels compared with NCD-fed mice, which were reduced after astrocyte SCAP deletion (Supplementary Fig. 8i).”

It may state two separate claims as one.

SCAP overexpression mediated increased phosphorylation levels of IκBα, indicating SCAP promotes phosphorylation of IκBα, paving the way for NF-κB activation.

“Consistently, SCAP overexpression also mediated the increased phosphorylation levels of IκBα (Supplementary Fig. 9a), indicating that SCAP promotes the phosphorylation of IκBα, paving the way for NF-κB activation.”

It may state two separate claims as one.

Immunofluorescence staining showed GOLPH3 (Golgi stress marker) was upregulated in SCAP overexpression group, accompanied by increase in p-IκBα.

“Meanwhile, immunofluorescence staining showed that Golgi phosphoprotein 3 (GOLPH3; a Golgi stress marker) was upregulated in the SCAP overexpression group, accompanied by an increase in p-IκBα (Supplementary Fig. 9e–g).”

It may state two separate claims as one.

Neurons cocultured with high-glucose and LDL-C-treated astrocytes (GFAP+/C3+) showed significantly elevated levels of apoptotic proteins Bax and cleaved caspase-3 and significantly reduced levels of antiapoptotic protein Bcl-2 compared with neurons cocultured with control astrocytes (GFAP+/C3−).

“Our results (Supplementary Fig. 3k, l) showed that compared with neurons cocultured with control astrocytes (GFAP+/C3−), neurons cocultured with high-glucose and LDL-C-treated astrocytes (GFAP+/C3+) showed significantly elevated levels of the apoptotic proteins Bax and cleaved caspase-3 and significantly reduced levels of the antiapoptotic protein Bcl-2.”

• AssumptionThe authors state this as an assumption: High glucose and LDL-C treatment of primary astrocytes simulates glycolipid abnormalities in T2DM.

It may state two separate claims as one.

There was no difference in swimming speed or total arms entries among the four groups.

“There was no difference in the swimming speed and total arms entries among the four groups (Supplementary Fig. 5i, l).”

It may state two separate claims as one.

Under high glucose and LDL-C treatment, neurons cocultured with SCAP-KOA exhibited increased synaptic density and increased axonal complexity compared with neurons cocultured with WTA astrocytes.

“Under the high glucose and LDL-C treatment, the neurons cocultured with SCAP-KOA exhibited increased synaptic density (Fig. 7f, h) and increased axonal complexity (Fig. 7g, i) compared with neurons cocultured with WTA astrocytes, suggesting that the inhibition of SCAP could suppress complement C3 signaling and astrocyte neurotoxicity.”

It may state two separate claims as one.

Spine density was significantly reduced in DG and CA3 regions of HFD/STZ mice but remained unchanged in CA1.

“The spine density was significantly reduced in the DG and CA3 regions of HFD/STZ mice (Fig. 2c, f) but remained unchanged in CA1 (Supplementary Fig. 2c).”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

In patients with T2DM, serum C3 levels were higher in those with mild cognitive impairment, showing a U-shaped correlation with LDL-C levels.

“In patients with T2DM, serum C3 levels were higher in those with mild cognitive impairment, showing a U-shaped correlation with low-density lipoprotein-cholesterol (LDL-C) levels.”

• AssumptionRests on an assumption: Serum C3 levels reflect brain C3 levels in T2DM patients.

It may state two separate claims as one.

A U-shaped relationship was observed between LDL-C and serum C3 concentrations (P = 0.047), with a cut-off point of 2.535 mmol/l.

“A U-shaped relationship was observed between LDL-C and serum C3 concentrations (P = 0.047; Supplementary Fig. 10d), with a cut-off point of 2.535 mmol/l (Supplementary Table 1), but no correlation with total cholesterol levels was observed (Supplementary Table 2 and Supplementary Fig. 10e).”

It may state two separate claims as one.

In SCAP-KOA, p-IκBα levels were reduced under combined high-glucose and LDL-C treatment, and p-IκBα expression in the Golgi was significantly decreased.

“In SCAP-KOA, p-IκBα levels were reduced under combined high-glucose and LDL-C treatment (Fig. 9h, i), and p-IκBα expression in the Golgi was significantly decreased (Fig. 9j).”

The quote only partly states this claim.

In the Y-maze, alternation triplets were impaired in Cre-, f/f HFD/STZ mice compared with NCD mice.

“Similarly, the alternation triplets in Y-maze (Supplementary Fig. 5m) and the recognition index in NOR test (Supplementary Fig. 5n, o) were impaired in Cre-, f/f HFD/STZ mice, but these deficits were improved in AS cKO HFD/STZ mice.”

It may state two separate claims as one.

C3 expression was notably increased in GFAP-positive astrocytes in the CA3 and DG regions, but not in CA1.

“Immunofluorescence staining confirmed that C3 expression was notably increased in GFAP-positive astrocytes in the CA3 (Fig. 2h–j) and DG regions (left panel of Supplementary Fig. 2f), but not in CA1 (right panel of Supplementary Fig. 2f), suggesting a neurotoxic astrocyte phenotype in the DACI model.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

The quote only partly states this claim.

In the NOR test, the recognition index was impaired in Cre-, f/f HFD/STZ mice compared with NCD mice.

“Similarly, the alternation triplets in Y-maze (Supplementary Fig. 5m) and the recognition index in NOR test (Supplementary Fig. 5n, o) were impaired in Cre-, f/f HFD/STZ mice, but these deficits were improved in AS cKO HFD/STZ mice.”

It may state two separate claims as one.

SCAP overexpression and rescue mediated NF-κB activation, as demonstrated by increased NF-κB phosphorylation after SCAP overexpression and rescue in SCAP KO models, as well as increased NF-κB nuclear translocation.

“We found that SCAP overexpression and rescue mediated NF-κB activation, as demonstrated by increased NF-κB phosphorylation after SCAP overexpression and rescue in SCAP KO models (Supplementary Fig. 8a,c), as well as increased NF-κB nuclear translocation (Supplementary Fig. 8e–h).”

It may state two separate claims as one.

Primary astrocytes treated with high-glucose and LDL-C showed increased C3 expression and increased C3 secretion into the medium, with immunofluorescence confirming elevated astrocytic C3 levels.

“The primary astrocytes treated with high-glucose and LDL-C showed an increased C3 expression (Supplementary Fig. 3f,g) and increased C3 secretion into the medium (Supplementary Fig. 3h), with immunofluorescence also confirming elevated astrocytic C3 levels (Supplementary Fig. 3i, j).”

• AssumptionThe authors state this as an assumption: High glucose and LDL-C treatment of primary astrocytes simulates glycolipid abnormalities in T2DM.

It may state two separate claims as one.

SCAP overexpression rescued the reduction of SCAP and complement C3 in the KO model, accompanied by activation of astrocytic reactive morphology with a stellate appearance.

“The data showed that SCAP overexpression rescued the reduction of SCAP and complement C3 in the KO model (Supplementary Fig. 7h,i), accompanied by the activation of astrocytic reactive morphology (Supplementary Fig. 7j), with a stellate appearance.”

It may state two separate claims as one.

Synapse density per 10 μm of dendrite was significantly elevated by C3aRA in WTA neurons; no additional effect was observed in KOA cocultures.

“Similarly, the synapse density per 10 μm of dendrite was significantly elevated by C3aRA in WTA neurons (Fig. 7m; P < 0.05); no additional effect was observed in KOA cocultures.”

It may state two separate claims as one.

SCAP deletion in KO astrocytes significantly inhibited NF-κB phosphorylation, nuclear translocation and binding to the C3 promoter region.

“Meanwhile, the SCAP deletion in KO astrocytes significantly inhibited NF-κB phosphorylation (Fig. 8j, k), nuclear translocation (Fig. 8l, m) and binding to the C3 promoter region (Fig. 8n).”

It may state two separate claims as one.

Overexpression of SCAP increased recruitment of IκBα to the Golgi region; colocalization of IκBα and Golgi97 was significantly higher than vector group.

“We confirmed that the overexpression of SCAP increased the recruitment of IκBα to the Golgi region; the colocalization of IκBα and Golgi97 was significantly higher than that of the vector group via confocal microscopy (Supplementary Fig. 9b–d).”

It may state two separate claims as one.

C3aRA preserved dendritic branching and spine density in WTA cultures, with no effect on neurons cultured with SCAP-KOA.

“The C3aRA preserved dendritic branching (Fig. 7j, top) and spine density (Fig. 7l, top) in WTA cultures, with no effect on neurons cultured with SCAP-KOA (Fig. 7j, l, bottom).”

It may state two separate claims as one.

Serum C3 levels were elevated in patients with T2DM and were associated with decreased global cognitive ability (MoCA score), episodic memory ability (LMT score) and learning and memory ability (AVLT DR score).

“In this Article, we found that serum C3 levels were elevated in patients with T2DM and were associated with decreased global cognitive ability (MoCA score), episodic memory ability (LMT score) and learning and memory ability (AVLT DR score).”

It may state two separate claims as one.

In cocultures, SCAP-KO reduced C3 elevation induced by high glucose and LDL-C, abrogating the neuroplastic changes in neurons.

“In cocultures, SCAP-KO reduced C3 elevation induced by high glucose and LDL-C, abrogating the neuroplastic changes in neurons.”

It may state two separate claims as one.

In astrocytes exposed to high-glucose and cholesterol treatment, NF-κB phosphorylation and nuclear translocation were observed, which thereby activates C3-C3aR.

“In this Article, NF-κB phosphorylation and nuclear translocation, which thereby activates C3-C3aR, were observed in astrocytes exposed to high-glucose and cholesterol treatment.”

It may state two separate claims as one.

The DG and CA3 regions are especially sensitive to chronic cholesterol accumulation, which may underlie the cognitive impairments in DACI-model mice.

“Our analysis confirms that the DG and CA3 regions, crucial for memory formation, are especially sensitive to chronic cholesterol accumulation, which may underlie the cognitive impairments in DACI-model mice61.”

• cites [61] Hainmueller, T. & Bartos, M. Dentate gyrus circuits for encoding, retrieval and discrimination of episodic memories. Nat. Rev. Neurosci. 21, 153–168 (2020). sourceCheck pending

It may state two separate claims as one.

SCAP deficiency alleviated cognitive dysfunction and impaired neuroplasticity compared with SCAP fl/fl DM-model mice.

“Although no significant changes in blood glucose, body weight or lipid parameters were observed, the SCAP deficiency alleviated cognitive dysfunction and impaired neuroplasticity compared with SCAP fl/fl DM-model mice.”

It may state two separate claims as one.

In DM-model mice, SCAP activation is confirmed in astrocytes, with increases in SCAP levels in the DG and CA3 regions where astrocytes showed atrophy.

“In this Article, we confirmed SCAP activation in astrocytes in DM-model mice, with increases in SCAP levels in the DG and CA3 regions, where astrocytes showed atrophy.”

It may state two separate claims as one.

In DACI-model mice, astrocytes in the CA3 and DG hippocampal regions showed reduced volume and surface area, increased soma volume and decreased complexity, suggesting an atrophic morphology linked to DACI.

“Our Article revealed that in DACI-model mice, astrocytes in the CA3 and DG hippocampal regions showed reduced volume and surface area, increased soma volume and decreased complexity, suggesting an atrophic morphology linked to DACI.”

It may state two separate claims as one.

NF-κB activation was abnormally activated in HFD/STZ-induced mice and inhibited by SCAP deletion.

“NF-κB activation, previously linked to astrocyte plasticity, was found to be abnormally activated in HFD/STZ-induced mice and inhibited by SCAP deletion.”

It may state two separate claims as one.

HFD/STZ-induced diabetic mice exhibited cognitive impairment with reduced neuronal complexity, fine spines and synaptic density, suggesting that impaired neuroplasticity may contribute to learning and memory deficits.

“The HFD/STZ-induced diabetic mice exhibited cognitive impairment with reduced neuronal complexity, fine spines and synaptic density, suggesting that the impaired neuroplasticity may contribute to learning and memory deficits.”

It may state two separate claims as one.

These changes were linked to improved synaptic plasticity and cognitive performance.

“These changes were linked to improved synaptic plasticity and cognitive performance.”

It may state two separate claims as one.

Knocking out SCAP in astrocytes increased astrocyte territory volume, dendritic complexity and synaptic coverage, similar to caloric-restriction-induced remodeling.

“We observed that knocking out SCAP in astrocytes increased astrocyte territory volume, dendritic complexity and synaptic coverage, similar to caloric-restriction-induced remodeling33.”

• cites [33] Popov, A. et al. Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus. Cell Death Dis. 11, 208 (2020). sourceCheck pending

It may state two separate claims as one.

SCAP knockdown increased synaptic density, correlating with enhanced astrocyte synaptic coverage.

“Furthermore, SCAP knockdown increased synaptic density, correlating with enhanced astrocyte synaptic coverage.”

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

Astrocytes can detect neurotoxic danger-associated molecules early in disease progression and become disease-associated astrocytes.

“Although not primarily immune cells, astrocytes can detect neurotoxic danger-associated molecules early in disease progression and undergo changes to become disease-associated astrocytes40.”

• cites [40] Habib, N. et al. Disease-associated astrocytes in Alzheimer’s disease and aging. Nat. Neurosci. 23, 701–706 (2020). sourceNot checked yet

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

Chronic overnutrition or sustained astrocytic IKKβ/NF-κB activation induces astrocytic process shortening, potentially contributing to metabolic syndrome.

“For example, chronic overnutrition or sustained astrocytic IKKβ/NF-κB activation in astrocytes has been shown to induce astrocytic process shortening, potentially contributing to the development of metabolic syndrome32.”

• cites [32] Zhang, Y., Reichel, J. M., Han, C., Zuniga-Hertz, J. P. & Cai, D. Astrocytic process plasticity and IKKβ/NF-κB in central control of blood glucose, blood pressure, and body weight. Cell Metab. 25, 1091–1102.e4 (2017). sourceCheck pending

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

Dysregulation of SCAP impairs cholesterol homeostasis and lipid metabolism, contributing to metabolic diseases such as obesity, T2DM and cardiovascular disorders.

“The dysregulation of SCAP impairs cholesterol homeostasis and lipid metabolism, contributing to metabolic diseases such as obesity, T2DM and cardiovascular disorders.”

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

The abundance of disease-associated astrocytes increases substantially as the disease progresses, contributing to inflammation and neurotoxicity.

“The abundance of disease-associated astrocytes increases substantially as the disease progresses, contributing to the inflammation and neurotoxicity41.”

• cites [41] Lee, H. G. et al. Author correction: disease-associated astrocyte epigenetic memory promotes CNS pathology. Nature 631, E8 (2024). sourceCheck pending

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

Inflammatory factors can increase SCAP expression, promoting translocation of the SCAP/SREBP2 complex from the ER to the Golgi apparatus, which disrupts cholesterol homeostasis and contributes to atherosclerosis and nonalcoholic fatty liver disease.

“Inflammatory factors can further increase SCAP expression, promoting the translocation of the SCAP/SREBP2 complex from the endoplasmic reticulum (ER) to the Golgi apparatus, which disrupts cholesterol homeostasis and contributes to conditions such as atherosclerosis21,22 and nonalcoholic fatty liver disease23.”

• cites [21] Chen, Y. et al. Inflammatory stress induces statin resistance by disrupting 3-hydroxy-3-methylglutaryl-CoA reductase feedback regulation. Arterioscler. Thromb. Vasc. Biol. 34, 365–376 (2014). sourceCheck pending
• cites [22] Ye, Q. et al. Inflammatory stress increases unmodified LDL uptake via LDL receptor: an alternative pathway for macrophage foam-cell formation. Inflamm. Res. 58, 809–818 (2009). sourceNot checked — no full text of the source
• cites [23] Ma, K. L. et al. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatology 48, 770–781 (2008). sourceNot checked — no full text of the source

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

SCAP is a cholesterol sensor that regulates intracellular cholesterol homeostasis through signal transduction.

“Sterol regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) is a cholesterol sensor that regulates intracellular cholesterol homeostasis through signal transduction16–18.”

• cites [16] Gong, Y. et al. Sterol-regulated ubiquitination and degradation of Insig-1 creates a convergent mechanism for feedback control of cholesterol synthesis and uptake. Cell Metab. 3, 15–24 (2006). sourceNot checked — no full text of the source
• cites [17] Yan, R. et al. Structural basis for sterol sensing by Scap and Insig. Cell Rep. 35, 109299 (2021). sourceCheck pending
• cites [18] Guo, C. et al. Cholesterol homeostatic regulator SCAP-SREBP2 integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling in macrophages. Immunity 49, 842–56.e7 (2018). sourceNot checked — no full text of the source

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

In neurodegenerative diseases such as AD, astrocytes undergo changes ranging from atrophy with functional loss to reactive astrogliosis characterized by hypertrophy, which leads to neurotoxicity and impairments in synaptic support.

“In neurodegenerative diseases, such as AD, astrocytes undergo complex changes, ranging from atrophy with functional loss to reactive astrogliosis characterized by hypertrophy, which leads to neurotoxicity and impairments in synaptic support34,35.”

• cites [34] Preman, P., Alfonso-Triguero, M., Alberdi, E., Verkhratsky, A. & Arranz, A. M. Astrocytes in Alzheimer’s disease: pathological significance and molecular pathways. Cells 10, 540 (2021). sourceNot checked yet
• cites [35] Verkhratsky, A., Marutle, A., Rodríguez-Arellano, J. J. & Nordberg, A. Glial asthenia and functional paralysis: a new perspective on neurodegeneration and Alzheimer’s disease. Neuroscientist 21, 552–568 (2015). sourceNot checked — no full text of the source

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

Caloric restriction enhances astrocyte dendritic complexity, expands astrocyte territories and increases the volume of perisynaptic leaflets, thereby improving glutamate clearance and K+ buffering, ultimately supporting synaptic plasticity.

“Conversely, caloric restriction enhances astrocyte dendritic complexity, expands astrocyte territories and increases the volume of perisynaptic leaflets, thereby improving glutamate clearance and K+ buffering, ultimately supporting synaptic plasticity33.”

• cites [33] Popov, A. et al. Caloric restriction triggers morphofunctional remodeling of astrocytes and enhances synaptic plasticity in the mouse hippocampus. Cell Death Dis. 11, 208 (2020). sourceCheck pending

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

SCAP dysfunction triggers inflammatory activation in macrophages.

“SCAP dysfunction also triggers an inflammatory activation in macrophages24,25.”

• cites [24] Li, L. C. et al. Cross-talk between TLR4-MyD88-NF-κB and SCAP-SREBP2 pathways mediates macrophage foam cell formation. Am. J. Physiol. Heart Circ. Physiol. 304, H874–H884 (2013). sourceNot checked — no full text of the source
• cites [25] Ouyang, N. et al. Dysfunction of cholesterol sensor SCAP promotes inflammation activation in THP-1 macrophages. Exp. Cell Res. 367, 162–169 (2018). sourceNot checked — no full text of the source

It may state two separate claims as one.

Abnormal cholesterol metabolism is associated with initiation of inflammation, amyloid-beta production and accumulation, tau protein phosphorylation and synaptic damage.

“Moreover, abnormal cholesterol metabolism is associated with the initiation of inflammation, amyloid-beta production and accumulation, tau protein phosphorylation and synaptic damage26,27.”

• cites [26] Rudajev, V. & Novotny, J. Cholesterol as a key player in amyloid β-mediated toxicity in Alzheimer’s disease. Front Mol. Neurosci. 15, 937056 (2022). sourceCheck pending
• cites [27] Wang, T. et al. High cholesterol and 27-hydroxycholesterol contribute to phosphorylation of tau protein by impairing autophagy causing learning and memory impairment in C57BL/6J mice. J. Nutr. Biochem. 106, 109016 (2022). sourceNot checked — no full text of the source

It may state two separate claims as one.

SCAP-mediated Golgi translocation activates NF-κB, regulating neuron-glial crosstalk via the NF-κB-C3-C3aR pathway, thereby restoring neuroplasticity.

“Mechanistically, SCAP-mediated Golgi translocation activates NF-κB, regulating neuron–glial crosstalk via the NF-κB–C3–C3aR pathway, thereby restoring neuroplasticity.”

It may state two separate claims as one.

Aberrant lipid metabolism, hyperglycemia and chronic neuroinflammation are key contributors to cognitive impairment in diabetes mellitus.

“The key contributors include aberrant lipid metabolism, hyperglycemia and chronic neuroinflammation8,48.”

• cites [8] Taskinen, M. R. Type 2 diabetes as a lipid disorder. Curr. Mol. Med. 5, 297–308 (2005). sourceNot checked — no full text of the source
• cites [48] Soran, H., Schofield, J. D., Adam, S. & Durrington, P. N. Diabetic dyslipidaemia. Curr. Opin. Lipido. 27, 313–322 (2016). sourceNot checked — no full text of the source

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

All in vitro experiments were conducted in triplicate.

“All in vitro experiments were conducted in triplicate.”

It may state two separate claims as one.

C3 upregulation was driven by SCAP activation, which occurred only under combined hyperglycemia and hypercholesterolemia; neither glucose nor cholesterol alone was sufficient to induce SCAP expression.

“This C3 upregulation was driven by SCAP activation, which occurred only under combined hyperglycemia and hypercholesterolemia; neither glucose nor cholesterol alone was sufficient to induce SCAP expression.”

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

All experiments were performed at least three times, and the findings were replicated in mice and cell cultures in each experiment.

“All experiments were performed at least three times, and the findings were replicated in mice and cell cultures in each experiment.”

It may state two separate claims as one.

Pathological astrocytic responses expressing C3 are likely to cause neuronal apoptosis in vitro, supporting the neurotoxic nature of C3-GFAP-double-positive astrocytes.

“These data suggest that pathological astrocytic responses expressing C3 are likely to cause neuronal apoptosis in vitro, supporting the neurotoxic nature of C3–GFAP-double-positive astrocytes.”

• AssumptionThe authors state this as an assumption: High glucose and LDL-C treatment of primary astrocytes simulates glycolipid abnormalities in T2DM.

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

All experimental procedures followed the ARRIVE guidelines, adhered to animal ethics standards and were approved by the Institutional Animal Care and Use Committee of Zhongda Hospital and Southeast University, China.

“All experimental procedures followed the Animal Research: Reporting of In Vivo Experiments guidelines, adhered to animal ethics standards and were approved by the Institutional Animal Care and Use Committee of Zhongda Hospital and Southeast University, China (approval no. 20210301022).”

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

The majority of patients with T2DM are obese and prone to hypercholesterolemia.

“The majority of patients with T2DM are obese and prone to hypercholesterolemia49.”

• cites [49] Hu, X. et al. The role of remnant cholesterol beyond low-density lipoprotein cholesterol in diabetes mellitus. Cardiovasc. Diabetol. 21, 117 (2022). sourceCheck pending

It may state two separate claims as one.

SCAP mediates pathological astrocytic responses via the NF-κB-C3 pathway, with the Golgi acting as the platform for SCAP-driven activation.

“These findings uncover a critical regulatory axis underlying astrocytic dysfunction, where SCAP mediates pathological astrocytic responses via the NF-κB–C3 pathway, with the Golgi acting as the platform for SCAP-driven activation.”

• AssumptionRests on an assumption: SCAP is predominantly expressed in astrocytes and neurons.

It may state two separate claims as one.

Astrocytes exhibit morphological atrophy and reduced presynaptic coverage under diabetic conditions, which may be related to impairment of synaptic plasticity.

“These data demonstrate that astrocytes exhibit morphological atrophy and reduced presynaptic coverage under diabetic conditions, which may be related to the impairment of synaptic plasticity.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

These findings indicate pathological astrocytic responses induced by HFD intake and STZ injection consistent with aging-related atrophy.

“These findings indicate pathological astrocytic responses induced by HFD intake and STZ injection consistent with aging-related atrophy.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

High glucose disrupts the cholesterol-mediated ER retention of SCAP, facilitating SCAP translocation to the Golgi, which is essential for NF-κB-C3 signaling activation.

“SCAP-Golgi colocalization aligns with NF-κB activation and C3 transcription, suggesting that the high glucose disrupts the cholesterol-mediated ER retention of SCAP, facilitating SCAP translocation to the Golgi, which is essential for NF-κB–C3 signaling activation.”

It may state two separate claims as one.

Elevated C3 is closely related to diabetes-related cognitive impairment clinically and both excessively high and low LDL-C are associated with elevated C3.

“These findings suggest that elevated C3 is closely related to diabetes-related cognitive impairment clinically and that both excessively high and low LDL-C are associated with elevated C3.”

• AssumptionRests on an assumption: Serum C3 levels reflect astrocytic C3 levels in the brain.
• AssumptionRests on an assumption: Findings in mouse models and cell cultures translate to human T2DM cognitive impairment.

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

Data were first evaluated for normality and equal variance, after which suitable statistical tests were selected.

“The data were first evaluated for normality and equal variance, after which suitable statistical tests were selected on the basis of these assessments.”

It may state two separate claims as one.

SCAP elimination in astrocytes mitigates astrocytic neurotoxic phenotypes (C3 expression and secretion), morphological atrophy (volume, area and branching complexity) and synaptic dysfunction (synapse coverage), thereby improving neuronal plasticity impairment in DACI-model mice.

“These findings demonstrate that SCAP elimination in astrocytes mitigates astrocytic neurotoxic phenotypes (C3 expression and secretion), morphological atrophy (volume, area and branching complexity) and synaptic dysfunction (synapse coverage), thereby improving neuronal plasticity impairment in DACI-model mice.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates key features of diabetes-associated cognitive impairment in humans.

It may state two separate claims as one.

NF-κB regulates C3 gene transcription and contributes to synaptic impairment through astrocyte process shortening.

“NF-κB, a transcription factor, could regulates C3 gene transcription38 and contributes synaptic impairment through astrocytes process shortening32.”

• cites [38] Lian, H. et al. NFκB-activated astroglial release of complement C3 compromises neuronal morphology and function associated with Alzheimer’s disease. Neuron 85, 101–115 (2015). sourceNot checked yet
• cites [32] Zhang, Y., Reichel, J. M., Han, C., Zuniga-Hertz, J. P. & Cai, D. Astrocytic process plasticity and IKKβ/NF-κB in central control of blood glucose, blood pressure, and body weight. Cell Metab. 25, 1091–1102.e4 (2017). sourceCheck pending

It may state two separate claims as one.

Inhibition of SCAP could suppress complement C3 signaling and astrocyte neurotoxicity.

“Under the high glucose and LDL-C treatment, the neurons cocultured with SCAP-KOA exhibited increased synaptic density (Fig. 7f, h) and increased axonal complexity (Fig. 7g, i) compared with neurons cocultured with WTA astrocytes, suggesting that the inhibition of SCAP could suppress complement C3 signaling and astrocyte neurotoxicity.”

It may state two separate claims as one.

SCAP upregulation can induce Golgi stress and provide a possible spatial basis for IκBα/NF-κB activation.

“These results suggest that SCAP upregulation can induce Golgi stress and provide a possible spatial basis for IκBα/NF-κB activation.”

It may state two separate claims as one.

DACI mice have altered neuronal morphology and impaired synaptic plasticity.

“These results indicate that DACI mice have altered neuronal morphology and impaired synaptic plasticity.”

• AssumptionRests on an assumption: The HFD/STZ mouse model recapitulates human T2DM and DACI.

It may state two separate claims as one.

Astrocytes in the DG and CA3 regions may be more sensitive and susceptible to metabolic and inflammatory stress responses, perhaps because they are involved in adult neurogenesis, active synaptic remodeling and higher basal neuronal plasticity.

“Astrocytes in the DG and CA3 regions may be more sensitive and susceptible to metabolic and inflammatory stress responses, perhaps because they are involved in adult neurogenesis, active synaptic remodeling and higher basal neuronal plasticity81,82.”

• cites [81] Grassi, D. et al. Nanoscale and functional heterogeneity of the hippocampal extracellular space. Cell Rep. 42, 112478 (2023). sourceCheck pending
• cites [82] Matias, I., Morgado, J. & Gomes, F. C. A. Astrocyte heterogeneity: impact to brain aging and disease. Front Aging Neurosci. 11, 59 (2019). sourceNot checked yet

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

The ER-to-Golgi translocation of the SCAP-SREBP2 complex is required for full activation of NLRP3.

“Notably, Guo et al. demonstrated that the ER-to-Golgi translocation of the SCAP–SREBP2 complex was required for the full activation of the NLRP318.”

• cites [18] Guo, C. et al. Cholesterol homeostatic regulator SCAP-SREBP2 integrates NLRP3 inflammasome activation and cholesterol biosynthetic signaling in macrophages. Immunity 49, 842–56.e7 (2018). sourceNot checked — no full text of the source

It may state two separate claims as one.

Greater lipid accumulation in CA3/DG could exacerbate astrocytic SCAP accumulation and NF-κB activation, leading to higher C3 production in those cells.

“Notably, CA3 (and the adjacent DG) experiences greater lipid accumulation under hyperglycemia conditions than CA183, which could exacerbate astrocytic SCAP accumulation and NF-κB activation, leading to higher C3 production in those cells.”

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

The exact molecular basis that leads to astrocyte heterogeneity in hippocampal subregions has not yet been elucidated.

“First, although we observed regional differences, we have not yet elucidated the exact molecular basis that leads to astrocyte heterogeneity in hippocampal subregions.”

It may state two separate claims as one.

The underlying mechanism involves the SCAP-mediated activation of the IκBɑ-NF-κB-C3 pathway, highlighting critical crosstalk between astrocytes and neurons.

“The underlying mechanism involves the SCAP-mediated activation of the IκBɑ–NF-κB–C3 pathway, highlighting the critical crosstalk between astrocytes and neurons.”

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

Depleting golgin-97 causes uncontrolled IκBα degradation and NF-κB activation.

“For NF-κB, Golgi structural proteins can modulate the pathway that depleting golgin-97 (a Golgi tethering factor) causes uncontrolled IκBα degradation and NF-κB activation89.”

• cites [89] Wang, J. et al. Trans-Golgi network tethering factors regulate TBK1 trafficking and promote the STING-IFN-I pathway. Cell Discov. 11, 23 (2025). sourceCheck pending

It may state two separate claims as one.

The mechanism linking LDL-C and C3 may lie in changes in lipid metabolism and immune regulation, thereby mediating complications such as cognitive impairment.

“In addition, we found that a U-shaped correlation between LDL-C and C3 levels is notable, suggesting that both excessively low and high LDL-C levels may cause elevated C3 in diabetes, and the mechanism may lie in changes in lipid metabolism and immune regulation, thereby mediating the occurrence of complications such as cognitive impairment.”

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

GOLPH3 potentiates Golgi stress and activates AKT/IKK, thereby enhancing NF-κB signaling in endotoxemia.

“Moreover, GOLPH3 has been shown to potentiate Golgi stress and activate AKT/IKK, thereby enhancing NF-κB signaling in endotoxemia90.”

• cites [90] Dusabimana, T. et al. GOLPH3 promotes endotoxemia-induced liver and kidney injury through Golgi stress-mediated apoptosis and inflammatory response. Cell Death Dis. 14, 458 (2023). sourceCheck pending

It may state two separate claims as one.

Astrocyte atrophy and reduced synaptic coverage are key factors in cognitive disorders.

“The evidence indicates that astrocyte atrophy and reduced synaptic coverage are key factors in cognitive disorders76,77.”

• cites [76] Tanaka, M. et al. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol. Brain 6, 6 (2013). sourceCheck pending
• cites [77] Perez-Alvarez, A., Navarrete, M., Covelo, A., Martin, E. D. & Araque, A. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34, 12738–12744 (2014). sourceCheck pending

It may state two separate claims as one.

Increased C3 expression in astrocytes may trigger local complement activation, thereby driving pathological synaptic elimination and neuronal damage, ultimately leading to cognitive deficits unique to DACI.

“Increased C3 expression in astrocytes may trigger local complement activation, thereby driving pathological synaptic elimination and neuronal damage62,85, ultimately leading to cognitive deficits unique to DACI.”

• cites [62] Jiang, T. et al. Reprogramming astrocytic NDRG2/NF-κB/C3 signaling restores the diabetes-associated cognitive dysfunction. eBioMedicine 93, 104653 (2023). sourceCheck pending
• cites [85] Shi, Q. et al. Complement C3 deficiency protects against neurodegeneration in aged plaque-rich APP/PS1 mice. Sci. Transl. Med. 9, eaaf6295 (2017). sourceNot checked yet

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

The Golgi apparatus is increasingly recognized as a platform for immune signal.

“The Golgi apparatus is increasingly recognized as a platform for immune signal88.”

• cites [88] Mărunţelu, I., Constantinescu, A. E., Covache-Busuioc, R. A. & Constantinescu, I. The Golgi apparatus: a key player in innate immunity. Int J. Mol. Sci. 25, 4120 (2024). sourceCheck pending

Probably not a substantial claim.

Canonical NF-κB activation requires SCAP-mediated Golgi translocation, coordinating with S1P/S2P proteases to activate SREBP1 and inflammatory responses.

“More recently, Fei et al. reported that canonical NF-κB activation requires SCAP-mediated Golgi translocation, coordinating with S1P/S2P proteases to activate SREBP1 and inflammatory responses86.”

• cites [86] Fei, X. et al. The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB. Cell Rep. 42, 112586 (2023). sourceNot checked — no full text of the source

It may state two separate claims as one.

Loss of SCAP attenuates lipopolysaccharide-induced IκBα phosphorylation and p65 nuclear entry, indicating that SCAP is essential for NF-κB activation independent of its lipid metabolism role.

“Consistently, a metabolic study noted that the loss of SCAP attenuates lipopolysaccharide -induced IκBα phosphorylation and p65 nuclear entry, indicating that SCAP is essential for NF-κB activation independent of its lipid metabolism role87.”

• cites [87] Lee, S. H., Lee, J. H. & Im, S. S. The cellular function of SCAP in metabolic signaling. Exp. Mol. Med. 52, 724–729 (2020). sourceCheck pending

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

These findings align with studies linking altered cholesterol exposure to impaired hippocampal synaptic plasticity.

“These findings align with studies linking altered cholesterol exposure to impaired hippocampal synaptic plasticity64,65.”

• cites [64] Korinek, M. et al. Cholesterol modulates presynaptic and postsynaptic properties of excitatory synaptic transmission. Sci. Rep. 10, 12651 (2020). sourceCheck pending
• cites [65] Loera-Valencia, R. et al. High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus. Sci. Rep. 11, 3736 (2021). sourceCheck pending

Probably not a substantial claim.

The DG and CA3 regions play key roles in memory encoding, pattern separation and retrieval.

“Given that the DG and CA3 regions play key roles in memory encoding, pattern separation and retrieval84, the regional increase in SCAP-C3 expression may have important functional implications.”

• cites [84] Ho, N., Sommers, M. S. & Lucki, I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci. Biobehav. Rev. 37, 1346–1362 (2013). sourceCheck pending

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

Reducing GOLPH3 alleviates Golgi stress and blunts NF-κB-driven inflammation.

“Conversely, reducing GOLPH3 alleviates Golgi stress and blunts NF-κB-driven inflammation.”

• cites [90] Dusabimana, T. et al. GOLPH3 promotes endotoxemia-induced liver and kidney injury through Golgi stress-mediated apoptosis and inflammatory response. Cell Death Dis. 14, 458 (2023). sourceCheck pending

It may state two separate claims as one.

The mechanistic link between organelle stress and inflammation connects SCAP with Golgi stress and NF-κB, providing a novel angle on how metabolic and stress signals converge on inflammation.

“This mechanistic link between organelle stress and inflammation underlines the significance of our work: it connects SCAP (a cholesterol trafficking protein) with Golgi stress and NF-κB, providing a novel angle on how metabolic and stress signals converge on inflammation.”

It may state two separate claims as one.

SCAP upregulation in DG and CA3 regions may be a response to local cholesterol demand or toxic accumulation, thereby promoting astrocytes to enter a reactive state.

“Thus, SCAP upregulation in these regions may be a response to local cholesterol demand or toxic accumulation, thereby promoting astrocytes to enter a reactive state.”

It may state two separate claims as one.

Increased expression of SCAP in astrocytes of diabetic mice leads to astrocyte atrophy, which impairs synaptic plasticity and contributes to cognitive decline.

“The increased expression of SCAP in astrocytes of diabetic mice leads to astrocyte atrophy, which impairs synaptic plasticity and contributes to cognitive decline.”

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

C3 and C3aR activation are implicated in AD and tau pathology, with C3aR inhibition mitigating neuronal defects.

“C3 and C3aR activation are implicated in AD and tau pathology, with C3aR inhibition mitigating neuronal defects74.”

• cites [74] Litvinchuk, A. et al. Complement C3aR inactivation attenuates tau pathology and reverses an immune network deregulated in tauopathy models and Alzheimer’s disease. Neuron 100, 1337–53.e5 (2018). sourceNot checked yet

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

The specific mechanism of abnormal astrocyte morphology and reduced complexity has not yet been clarified.

“Secondly, the specific mechanism of abnormal astrocyte morphology and reduced complexity has not yet been clarified, and single-cell transcriptomics or spatial transcriptomics will be used to further clarify the specific molecular mechanism in the future.”

It may state two separate claims as one.

Astrocyte atrophy results in decreased territory size and synaptic coverage, impairing synaptic plasticity and contributing to cognitive dysfunction.

“Astrocyte atrophy results in decreased territory size and synaptic coverage, impairing synaptic plasticity and contributing to cognitive dysfunction.”

• cites [76] Tanaka, M. et al. Astrocytic Ca2+ signals are required for the functional integrity of tripartite synapses. Mol. Brain 6, 6 (2013). sourceCheck pending
• cites [77] Perez-Alvarez, A., Navarrete, M., Covelo, A., Martin, E. D. & Araque, A. Structural and functional plasticity of astrocyte processes and dendritic spine interactions. J. Neurosci. 34, 12738–12744 (2014). sourceCheck pending

Probably not a substantial claim.

Inhibition of SCAP may represent a promising approach to mitigate DACI-related cognitive deficits.

“In summary, SCAP functions as a key regulator of astrocytic responses in DACI, promoting cognitive impairment through the activation of the IκBɑ–NF-κB–C3 pathway, and its inhibition may represent a promising approach to mitigate DACI-related cognitive deficits.”

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

The CA1 region may not trigger a similar upregulation of SCAP due to a lower initial metabolic load or more efficient cholesterol homeostasis mechanisms.

“At the same time, the CA1 region may not trigger a similar upregulation of SCAP due to a lower initial metabolic load or more efficient cholesterol homeostasis mechanisms.”

It may state two separate claims as one.

Both excessively low and high LDL-C levels may cause elevated C3 in diabetes.

“In addition, we found that a U-shaped correlation between LDL-C and C3 levels is notable, suggesting that both excessively low and high LDL-C levels may cause elevated C3 in diabetes, and the mechanism may lie in changes in lipid metabolism and immune regulation, thereby mediating the occurrence of complications such as cognitive impairment.”

It may state two separate claims as one.

SCAP activation exacerbates inflammation via the C3 pathway, further impairing neuroplasticity and resulting in learning and memory deficits.

“SCAP activation exacerbates inflammation via the C3 pathway, further impairing neuroplasticity and resulting in learning and memory deficits.”

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

Astrocytes can adapt to lifestyle changes, offering clinical benefits.

“Emerging evidence suggests astrocytes can adapt to lifestyle changes, offering clinical benefits30,31.”

• cites [30] Beauquis, J. et al. Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp. Neurol. 239, 28–37 (2013). sourceNot checked — no full text of the source
• cites [31] Rodríguez, J. J., Terzieva, S., Olabarria, M., Lanza, R. G. & Verkhratsky, A. Enriched environment and physical activity reverse astrogliodegeneration in the hippocampus of AD transgenic mice. Cell Death Dis. 4, e678 (2013). sourceNot checked yet

Probably not a substantial claim.

The Golgi apparatus, as a signaling hub for NF-κB, is essential for NF-κB-C3 activation.

“Recent findings highlight that the Golgi apparatus, as a signaling hub for NF-κB, is essential for NF-κB–C3 activation20,86.”

• cites [20] Huang, X. et al. Macrophage SCAP contributes to metaflammation and lean NAFLD by activating STING–NF-κB signaling pathway. Cell. Mol. Gastroenterol. Hepatol. 14, 1–26 (2022). sourceCheck pending
• cites [86] Fei, X. et al. The Scap-SREBP1-S1P/S2P lipogenesis signal orchestrates the homeostasis and spatiotemporal activation of NF-κB. Cell Rep. 42, 112586 (2023). sourceNot checked — no full text of the source

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

Complement proteins, including C1q and C3, are upregulated in AD brain tissues and cerebrospinal fluid, where they are pivotal in neuroinflammation and synapse elimination.

“Complement proteins, including C1q and C3, are upregulated in AD brain tissues36 and cerebrospinal fluid87,91, where they are pivotal in neuroinflammation and synapse elimination88,92.”

• cites [36] Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017). sourceNot checked yet
• cites [87] Lee, S. H., Lee, J. H. & Im, S. S. The cellular function of SCAP in metabolic signaling. Exp. Mol. Med. 52, 724–729 (2020). sourceCheck pending
• cites [91] Wu, T. et al. Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and tauopathy. Cell Rep. 28, 2111–23.e6 (2019). sourceNot checked yet
• cites [88] Mărunţelu, I., Constantinescu, A. E., Covache-Busuioc, R. A. & Constantinescu, I. The Golgi apparatus: a key player in innate immunity. Int J. Mol. Sci. 25, 4120 (2024). sourceCheck pending
• cites [92] Wu, J. et al. Microglial over-pruning of synapses during development in autism-associated SCN2A-deficient mice and human cerebral organoids. Mol. Psychiat. 29, 2424–2437 (2024). sourceCheck pending

It may state two separate claims as one.

Maintaining LDL-C levels within an optimal range could be crucial for controlling C3-associated neuroinflammation, which may affect treatment strategies focused solely on lowering LDL-C.

“This implies that maintaining LDL-C levels within an optimal range could be crucial for controlling C3-associated neuroinflammation, which may affect treatment strategies focused solely on lowering LDL-C.”