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LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer’s Disease
Open accessAbstract
SUMMARY The expression of some proteins in the autophagy pathway decline with age, which may impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5+, clathrin+ endosomes containing β-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition was associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from β-amyloid deposition.
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TL;DR
The paper identifies LC3-associated endocytosis (LANDO), a non-canonical autophagy-protein-dependent process in microglia that conjugates LC3 to Rab5+/clathrin+ endosomes containing β-amyloid and supports recycling of Aβ receptors. Loss of LANDO, but not canonical autophagy, exacerbates Aβ deposition, neuroinflammation, tau pathology, neurodegeneration, and memory deficits in 5xFAD mice.
Key findings
- LANDO requires ATG5 and Rubicon, but not FIP200, for LC3 recruitment to Aβ-containing endosomes; ATG5- or Rubicon-deficient BV2 microglia showed reduced LC3 recruitment and membrane-associated LC3, while FIP200 deficiency did not.
- In 4-month-old 5xFAD mice, myeloid ATG5 deficiency and global or microglia-specific Rubicon deficiency increased hippocampal and cortical Aβ plaque number/size, pro-inflammatory cytokines (TNFα, IL-1β, IL-6), reactive microgliosis, and tau hyperphosphorylation; myeloid or microglial FIP200 deficiency had no effect.
- LANDO-deficient cells showed impaired secondary Aβ uptake and abrogated recycling of CD36, TLR4, and TREM2, while primary Aβ uptake, Aβ degradation, endosome maturation, and lysosome association were unaffected.
- LANDO-deficient 5xFAD mice displayed accelerated neurodegeneration: reduced NeuN+ hippocampal neurons, increased cleaved-caspase 3 in CA3, impaired hippocampal synaptic transmission and LTP, and behavioral/memory deficits; Rubicon-deficient mice showed anhedonia as young as 2.5 months and approximately 50% sucrose preference by 4 months.
Methods
- Murine AD model: 5xFAD mice crossed with myeloid LysM-Cre conditional FIP200 or ATG5, germline Rubicon−/−, or CX3CR1-creERT2 conditional Rubicon/FIP200; experiments used mixed-sex cohorts at 4 months unless noted, on >97% C57BL/6J background.
- Cell and biochemical assays: BV2 microglia, RAW264.7 macrophages, primary BMDMs and microglia; CRISPR/Cas9 knockouts, GFP-LC3, oligomeric Aβ1-42, microscopy, flow cytometry, immunoblot, qPCR, ELISA, pH-rodo maturation, receptor recycling, Aβ uptake, electrophysiology, and behavior (sucrose preference, Y-maze, novel object recognition).
- Statistics: GraphPad Prism 7.0, powered to at least 0.8 by G*Power, significance at p < 0.05.
Limitations
- Stated: the 5xFAD models cannot fully exclude a role for infiltrating peripheral monocytes in Aβ clearance and neuroinflammation; CX3CR1-creERT2 transient ablation may not completely exclude Rubicon-deficient peripheral monocytes entering the brain before reconstitution.
- Stated: the receptor-recycling assay does not evaluate LANDO’s role in receptor degradation or other endosome-trafficking perturbations, and altered receptor signaling could promote cytokine expression; the authors also cannot formally exclude LAP functions in Aβ clearance/response in vivo.
- Evident from the text: findings are based on murine 5xFAD models and cultured cell systems, with no human validation reported; the authors also note tamoxifen may reduce Aβ oligomerization as a possible confound in MG-cre animals.
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In the paper
“Primary microglia isolated from LysM-Cre+ FIP200fl/fl and ATG5fl/fl mice (referred to as FIP200,cre+ and ATG5,cre+) showed a significant reduction in mRNA and protein expression when compared to LysM-Cre− littermates (Fig. S1A,B).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology
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In the paper
“In contrast, another requisite autophagy protein, RB1-inducible coiled-coil protein 1, also called FIP200 (herein, FIP200), has no such function.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
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In the paper
“We employed an established murine model of AD and found that in the myeloid compartment (including microglia), the autophagy protein, ATG5, promoted protection from Aβ accumulation, neuroinflammation, and neurodegeneration.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
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In the paper
“In dissecting these effects, we identified a novel form of RME and receptor recycling characterized by association of LC3/GABARAP-family proteins (herein, “LC3”) with endosomal membranes, a process we call LC3-Associated eNDOcytosis (LANDO).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
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In the paper
“Strikingly, a protein that constrains canonical autophagy, Rubicon, was similarly required for the protective effects.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
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In the paper
“Therefore, we analyzed FIP200 and ATG5 protein expression in primary neurons from both FIP200 and ATG5 genotypes using LysM-cre and observed no changes in endogenous expression levels (Fig. S1C).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology
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In the paper
“A potent hyperactivation of TNFα, IL1-β and IL-6 was observed at both the mRNA (Fig. 3E) and protein levels (Fig. 3F) upon Aβ1-42 exposure in Rubicon−/− microglia.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Rubicon-deficiency dramatically reduced recycling of TREM2 (Fig. 2J,K).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, in 5xFAD Rubicon-deficient mice, analysis of microglia-plaque association revealed an increase in plaque-associated microglia (Fig. 4F), suggestive of progressive gliosis in response to Aβ.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Strikingly, those genotypes that displayed defective receptor recycling showed a dramatically elevated TNFα, IL-1β, and IL-6 response to Aβ1-42 (Fig. 3C).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
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- It may state two separate claims as one. 48
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the absence of Rubicon either globally or conditionally in microglia, or myeloid ATG5 (but not myeloid or microglial FIP200), we observed accelerated disease pathology and neurodegeneration, reactive microgliosis, tau pathology, and behavioral impairment.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
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In the paper
“Consistent with this notion and similar to mice deficient in myeloid ATG5, 5xFAD Rubicon−/− mice and 5xFAD Rubicon MG-cre+ mice displayed an increase in Aβ plaque number and plaque size compared to either Rubicon+/− or MG-cre− littermates (Fig. 1A-D and S1I).”
- Also stated in: § ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology · plain
“Likewise, both 5xFAD ATG5 LysM-cre+, 5xFAD Rubicon−/−, and 5xFAD Rubicon MG-cre+ mice showed early accumulation of Aβ within the cortex, whereas mice deficient for myeloid or microglial FIP200 were unaffected compared to LysM- or MG-cre− littermates (Fig. 1E,F and Fig. S1J,K).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Primary microglia isolated from 5xFAD, Rubicon and FIP200, CX3CR1-creERT2 mice treated with tamoxifen at one month of age and allowed to reconstitute for 3 months (herein referred to as MG-cre+) showed ablation of Rubicon (Fig. S1F,G) or FIP200 (Fig. S1G), as indicated. In contrast, expression of each gene was restored in peripheral, splenic macrophages (Fig. S1H), as expected.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology
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In the paper
“Ablation of Beclin1, VPS34, ATG5, or ATG7, required for both autophagy and LAP, prevented recycling of TLR4, TREM2, and CD36, as did Rubicon, required for LAP but not autophagy (Martinez et al., 2015). In contrast, no effects were seen upon ablation of ULK1, FIP200, or ATG14, all required for autophagy, but dispensable for LAP (Martinez et al., 2015).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
What the sources say
- Not checked yetcites Martinez et al., 2015 source
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In the paper
“Consistent with our clearance assay, the loss of FIP200, ATG5, or Rubicon had no effect on primary uptake of Aβ (Fig. 2G). We next added TAMRA-labeled Aβ1-42 and allowed for a second round of RME to occur. Again, we quantified the amount of internalized TAMR-1-42 and observed a reduction in secondary uptake in ATG5 and Rubicon-deficient cells but not those deficient in FIP200 (Fig. 2G).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
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In the paper
“Neither microglial activation nor pro-inflammatory cytokine expression were altered in mice deficient in the 5xFAD transgene (Fig. S5A,B).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“We observed that over 90% of CD11b+ cells in brains from the 5xFAD Rubicon+/− and−/− mice were TMEM119+ (a microglia-specific marker (Bennett et al., 2016)) (Fig. S5C,D). Furthermore, the TMEM119+ cells isolated from 5xFAD Rubicon−/− mice had higher Iba1 expression compared to Rubicon+/− animals (Fig. S5E).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
What the sources say
- Not checked yetcites Bennett et al., 2016 source
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In the paper
“Using Iba1 expression as a positive control, we observed significant increases in TNFα, IL-1β, IL-6, and a marginal increase in CCL5 within the hippocampus of 5xFAD Rubicon−/− and myeloid ATG5-deficient mice compared to control littermates (Fig. 4G).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“FIP200-deficiency failed to have any impact on cytokine expression in response to Aβ1-42 (Fig. 3D). However, loss of LANDO in both ATG5 and Rubicon-deficient cells resulted in a robust increase in all four pro-inflammatory genes evaluated (Fig. 3D).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with our in vitro findings, myeloid or microglia-specific FIP200-deficiency had no effect on the extent of Iba1 expression in either the hippocampus or cortex of 5xFAD mice (Fig. 4A-C). In contrast, microglial hyperactivation was present in 5xFAD mice deficient in either Rubicon or myeloid ATG5 (Fig. 4A,B).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
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In the paper
“As expected, BV2 cells treated with Aβ1-42 had elevated pro-inflammatory gene expression, including IL-1β, IL-6, CCL5, and TNFα as reported (Pan et al., 2011) and consistent with human disease.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
What the sources say
- Not checked yetcites Pan et al., 2011 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with these reports, in the absence of Rubicon and ATG5, maturation of phagosomes was diminished as determined using pH-rodo-labeled zymosan, while maturation of endosomes containing pH-rodo-labeled Aβ was unaffected (Fig. 2E, S2E).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with what we observed with cultured cells (Fig. 3), Rubicon- or myeloid ATG5-deficiency led to significant upregulation of pro-inflammatory cytokines at the transcriptional level in the brain, whereas myeloid FIP200-deficiency had no effect.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
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In the paper
“To further explore this phenomenon, we employed the RAW264.7 myeloid cell line, and found that TLR4, TREM2, and CD36 effectively recycled to the plasma membrane following antibody-induced internalization. This recycling was dramatically impaired upon CRISPR/Cas9-mediated ablation of Rubicon or ATG5, upon expression of a dominant negative ATG4, or upon expression of the LC3-specific protease, RavZ”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In BV2 microglia, depletion of FIP200 had no effect on either the surface expression, internalization (Fig. S2D), or recycling of CD36, TLR4, or TREM2 (Fig. 2H,I). Strikingly, ablation of either ATG5 and Rubicon led to abrogation of recycling for all three receptors (Fig. 2H,I) while initial surface expression and internalization were unaffected (Fig. S2D).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Contrary to our assumptions, however, ablation of either ATG5 or Rubicon had no effect on either the endocytosis or degradation of Aβ (Fig. 2D).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed that both global and microglia-specific deletion of Rubicon and myeloid-specific deletion of ATG5 resulted in exacerbated Aβ deposition and plaque formation, reactive microgliosis, tau hyperphosphorylation, and neuronal cell death and dysfunction, leading to significant memory impairment.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD mouse model is a well-characterized model of Aβ aggregate deposition and Alzheimer's disease.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, while LAP functions to promote phagosome maturation and cargo destruction (Heckmann et al., 2017), we observed no effects of our deletions on the rate of Aβ degradation, endosome maturation, or lysosome association (Fig. 2).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“No variations in total fluid intake between genotypes was observed (Fig. 7B).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficiency accelerates behavioral and memory impairment in 5xFAD mice
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We found that 5xFAD Rubicon−/− mice showed a reduction in hippocampal synaptic transmission and, as a consequence, impaired long-term potentiation (LTP) when compared to littermate controls (Fig. 6E,F).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5XFAD mice display accelerated neuronal death and impaired neuronal function
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Myeloid or microglia-specific FIP200 depletion had no impact on tau phosphorylation, however loss of either Rubicon (global or microglia-specific) or myeloid ATG5 promoted tau phosphorylation throughout the hippocampus (Fig. 5A,C, S6A) and the cerebral cortex (Fig. 5B,D, S6B).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5xFAD mice have robust tau pathology
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed that both global and microglia-specific deletion of Rubicon and myeloid-specific deletion of ATG5 resulted in exacerbated Aβ deposition and plaque formation, reactive microgliosis, tau hyperphosphorylation, and neuronal cell death and dysfunction, leading to significant memory impairment.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD mouse model is a well-characterized model of Aβ aggregate deposition and Alzheimer's disease.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because we observed the association of LC3 and the endosomal markers Rab5 and clathrin at the membranes of Aβ-containing endosomes that was not altered by inhibition of phagocytosis, we called this LANDO.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed that both global and microglia-specific deletion of Rubicon and myeloid-specific deletion of ATG5 resulted in exacerbated Aβ deposition and plaque formation, reactive microgliosis, tau hyperphosphorylation, and neuronal cell death and dysfunction, leading to significant memory impairment.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD mouse model is a well-characterized model of Aβ aggregate deposition and Alzheimer's disease.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“5xFAD Rubicon−/− microglia-specific Rubicon-deficient, and myeloid ATG5-deficient mice all displayed a decrease in NeuN+ hippocampal neurons (Fig. 6A,B). FIP200-deficiency had no impact on neuronal number.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5XFAD mice display accelerated neuronal death and impaired neuronal function
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed that both global and microglia-specific deletion of Rubicon and myeloid-specific deletion of ATG5 resulted in exacerbated Aβ deposition and plaque formation, reactive microgliosis, tau hyperphosphorylation, and neuronal cell death and dysfunction, leading to significant memory impairment.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The 5xFAD mouse model is a well-characterized model of Aβ aggregate deposition and Alzheimer's disease.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We further found that Rubicon, ATG5, ATG7, and ATG4 were required, while ULK1, FIP200, and ATG14 were dispensable for this effect.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, loss of LANDO affected secondary uptake of Aβ, leading to increased extracellular deposition, and it is plausible that these deposits signal at the cell surface via other receptors to promote inflammatory signaling.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, the use of CX3CR1- creERT2 to transiently ablate Rubicon resulted in Rubicon-deficient microglia but Rubicon-sufficient splenic macrophages at 4-months of age, but does not completely exclude the possibility that Rubicon-deficient peripheral monocytes may have entered the brain prior to reconstitution of this population from the bone marrow.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The expression of several autophagy proteins, in particular Beclin1, ATG5, and ATG7, decline with age, and is exacerbated in AD (Lipinski et al., 2010; Lucin et al., 2013; Pickford et al., 2008; Rubinsztein et al., 2011).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In response to Aβ, LANDO supports the clearance of Aβ deposits and prevents microglial activation, such that in its absence, inflammatory cytokine production and neurodegeneration proceed unchecked.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Pro-inflammatory cytokines and chemokines secreted into the immediate neurological environment accelerate neuronal injury and eventually neuron death (Aktas et al., 2007; Heckmann et al., 2018; Morales et al.,2014).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Rubicon has been shown to be an inhibitor of canonical autophagy (Matsunaga et al., 2009) and a key component of a non-canonical function of autophagy proteins that modulates inflammatory immune activation (Cunha et al., 2018; Martinez et al., 2016).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > ATG5 and Rubicon-deficiency exacerbate Aβ deposition and pathology
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Microglia are the principal mediators of inflammation in response to Aβ accumulation (Machado et al., 2016; Perry and Holmes, 2014; Wang et al., 2015a), and their contribution to neuroinflammation is highly correlated to the progression of neurodegeneration and synaptic dysfunction, particularly with respect to Alzheimer’s disease (AD).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > INTRODUCTION
What the sources say
- Not checked yetcites Machado et al., 2016 source
- Not checked yetcites Perry and Holmes, 2014
- Not checked yetcites Wang et al., 2015a
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken as a whole, these data suggest LANDO may contribute to not only the regulation of aberrant Aβ deposition but also the immune activation of microglial cells in response to Aβ exposure.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“A marker of progressive AD in both humans and mice is the hyperphosphorylation of the microtubule-stabilizing protein tau. The incidence of tau phosphorylation increases as disease progresses and leads to microtubule de-stabilization and failure of the microtubule architecture, especially within neuronal axons (Frost et al., 2015; Gong and Iqbal, 2008; Noble et al., 2013).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5xFAD mice have robust tau pathology
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Taken together, these data suggest that both ATG5 and Rubicon are necessary for recruitment of LC3 to Aβ-containing endosomes, whereas FIP200 is dispensable.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, the requirements for recycling of these receptors to the plasma membrane appear to be identical to those for LAP and distinct from those of autophagy.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Since we have previously shown a vital role for LAP in regulating inflammatory immune responses (Martinez et al., 2016), we hypothesized that defective LANDO may have a similar effect.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO protects against Aβ-induced microglial activation
What the sources say
- Not checked yetcites Martinez et al., 2016 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Inhibition of actin polymerization and phagocytosis using latrunculin A (de Oliveira and Mantovani, 1988; Oliveira et al., 1996), prevented the internalization of the phagocytic substrate zymosan but had no effect on either the endocytic substrate dextran or Aβ (Fig. 2C), suggesting that uptake of Aβ in our model occurs primarily through endocytosis (RME).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
What the sources say
- Not checked yetcites de Oliveira and Mantovani, 1988
- Not checked yetcites Oliveira et al., 1996 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, LANDO facilitates the recycling of internalized Aβ receptors to the plasma membrane, supporting continued rounds of endocytosis.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on the association of LC3 to Aβ-containing endosomes, we propose the term LC3-Associated eNDOcytosis (LANDO) to describe this effect and suggest that LANDO is distinct from LAP and may have a unique role in Aβ clearance in vivo.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LC3 is recruited to endosomes containing Aβ.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Therefore, our results strongly suggest a role for microglial Rubicon and ATG5 in the clearance of Aβ and mitigation of microglial activation that is distinct from their functions in canonical autophagy.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“which can be analyzed in mice using a sucrose preference test (SPT) (Briones et al., 2012; Liu et al., 2018).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficiency accelerates behavioral and memory impairment in 5xFAD mice
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This region has been implicated as one of the first sites of neuronal dysfunction and neuronal death in AD (Belvindrah et al., 2014; Padurariu et al., 2012; Zhang et al., 2013).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5XFAD mice display accelerated neuronal death and impaired neuronal function
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Because tau phosphorylation is likely to promote axonal degeneration and eventual neuronal death, we analyzed cell death within the brains of our 5xFAD models.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficient 5XFAD mice display accelerated neuronal death and impaired neuronal function
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These analyses illustrate the importance for the molecular regulation of microglial function by LANDO in maintaining CNS integrity and immune function upon Aβ deposition, allowing for homeostasis in memory and behavior.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficiency accelerates behavioral and memory impairment in 5xFAD mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our data support a physiological role for LANDO in microglia in the mitigation and protection against microglial activation and immune-mediated aggregate Aβ) removal.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficiency accelerates behavioral and memory impairment in 5xFAD mice
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In advanced AD, patients often complain of anhedonia, or the inability to sense or experience pleasure (Naudin et al., 2015; Reichman and Coyne, 1995)”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > RESULTS > LANDO-deficiency accelerates behavioral and memory impairment in 5xFAD mice
What the sources say
- Not checked yetcites Naudin et al., 2015 source
- Not checked yetcites Reichman and Coyne, 1995
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, all animals were generated on the C57BL/6J background which was confirmed by microsatellite analysis, therefore the differences observed do not reflect a background effect between strains.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In turn, increased cytokines, such as interleukin-1, can influence Aβ uptake (Mrak and Griffin, 2000; Shaftel et al., 2007).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Mrak and Griffin, 2000
- Not checked yetcites Shaftel et al., 2007 source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Similar effects were observed in response to dying cells in macrophages lacking Rac1 or the efferocytosis receptors merTK and TIM4 (Cai et al., 2018; Camenisch et al., 1999; Martinez et al., 2011; Scott et al., 2001; Thorp et al., 2008), consistent with this idea.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
What the sources say
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“A previous study had shown that this recycling of CD36 and TREM2 is dependent on Beclin1 and VPS34 (Lucin et al., 2013), which we confirmed in primary BMDM (Fig. 3).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Lucin et al., 2013 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Whole body acute deletion of ATG7 causes lethal neuronal degeneration (Karsli-Uzunbas et al., 2014).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
What the sources say
- Not checked yetcites Karsli-Uzunbas et al., 2014 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Based on our findings using myeloid ATG5-deficiency and conditional ablation of Rubicon in microglia, we suggest that LANDO functions in microglia not only to promote Aβ clearance but also to promote an anti-inflammatory immune response.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“While autophagy proteins have been shown to impact the clearance of protein aggregates in neurons, most likely by the canonical autophagic process of aggrephagy (Frake et al., 2015; Menzies et al., 2017; Qaisiya et al., 2017; Sarkar et al., 2007; Sarkar et al., 2009; Webb et al., 2003; Yamamoto and Simonsen, 2011), effects in microglia of the CNS are more likely due to LANDO.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
What the sources say
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The assay used herein does not evaluate the role of LANDO in receptor degradation, or other potential perturbations in endosome trafficking, and it remains possible that such alterations alter receptor signaling to promote cytokine expression in response to Aβ.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We conclude that LANDO is distinct from canonical autophagy and plays a requisite role in the recycling of putative Aβ receptors.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“BV2 microglia deficient in FIP200, ATG5, and Rubicon were generated using CRISPR/Cas9 technology by lentiviral transduction and puromycin selection.”
- Also stated in: § METHOD DETAILS · plain
“BV2 cells were subsequently transduced and transduction efficiency was confirmed by immunoblot analysis following two weeks of puromycin selection.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
- Also stated in: § METHOD DETAILS · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All experiments were designed and are powered to a minimum of 0.8 as calculated using G*Power.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“This assay has been well-established and verified previously (Eng et al., 2010; He et al., 2009; Martinez et al., 2015).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
What the sources say
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Following the above protocol, fluorescent signal from recycled receptors is intracellular and readily determined by fluorescent microscopy as described above.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“MG-cre− animals used in the present study have been exposed to tamoxifen and allowed the same reconstitution period as the MG-cre+ mice to ensure no off-target effects from tamoxifen administration.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > EXPERIMENTAL MODEL & SUBJECT DETAILS
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Specificity of the antibody targeting the primary β-amyloid receptor TREM2 was confirmed by staining wild-type and TREM2 −/− BV2 microglial cells (data not shown).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All strains used had an overall background identity of greater than 97%.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > EXPERIMENTAL MODEL & SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All the cell lines used were confirmed as mycoplasma negative using MycoAlert Mycoplasma Detection kit (Lonza #LT07).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > EXPERIMENTAL MODEL & SUBJECT DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“This method is well-established and used as previously reported (Lucin et al., 2013).”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
What the sources say
- Not checked yetcites Lucin et al., 2013 source
Strength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice with less than 5 arm entries during the 5 min. trial were excluded from the analysis.”
§ LC3-associated endocytosis facilitates β-amyloid clearance and mitigates neurodegeneration in murine Alzheimer’s Disease > STAR METHODS > METHOD DETAILS
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
BV2 murine microglial cells are a valid model of primary microglia for studying LANDO and Aβ responses.
“we engineered BV2 murine microglial cells expressing GFP-LC3 that are deficient in FIP200, ATG5, or Rubicon using CRISPR/Cas9 (Fig. S2A).”
The paper relies on this without support.
The 5xFAD mouse model is a well-characterized model of Aβ aggregate deposition and Alzheimer's disease.
“We employed a well-characterized model of Aβ aggregate deposition, the 5xFAD AD mouse model with genetic manipulation of our target autophagy-related genes.”
The paper relies on this without support.
The behavioral tests used are well-characterized and known to be affected at late stages in the 5xFAD model.
“We therefore subjected mice to a variety of well-characterized behavioral tests known to be affected at late stages in the 5xFAD model.”
The paper relies on this without support.
The commercially available antibodies for CD36, TLR4, and TREM2 used in the recycling experiments are validated and specific.
“Furthermore, validated commercially available antibodies for CD36, TLR4, and TREM2 were used for all recycling experiments.”
The paper relies on this without support.
Latrunculin A inhibits phagocytosis but not endocytosis, allowing delineation between the two processes.
“To delineate between phagocytosis and endocytosis, cells were treated as indicated with the phagocytic inhibitor latrunculin A.”
The paper relies on this without support.
Zymosan is a specific control substrate for phagocytosis and dextran is a specific control substrate for endocytosis.
“The following control substrates were used, zymosan (phagocytosis) and dextran (endocytosis)”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Considerable evidence has found that microglia promote the uptake and degradation of Aβ.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [146]
In the citing paper
“Consistent with previous reports [50, 118], further accumulation of LC3-II and p62 was observed in 5xFAD mice when compared to WT mice.”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [50]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Conflicting sources for BV2 cells
MinorThe key resources table lists Washington University as the source of BV2 microglia, but the methods state that the BV2 cells were obtained from ATCC.
“| BV2 murine microglia | Washington University | Herbert Virgin |”
“BV2 murine microglia and RAW264.7 cells were obtained from ATCC.”
Citations
Cites
3 retracted
Martinez, J., Malireddi, R. K. S., Lu, Q., Cunha, L. D., Pelletier, S., Gingras, S., Orchard, R., Guan, J.-L., Tan, H., Peng, J., et al. (2015) · Nature Cell Biology · doi:10.1038/ncb3192 · Cited by 758 · cited 17×
“Deficiencies in LAP have been shown to reduce the ability of a cell to degrade phagosome cargo, including dying cells, fungi, and bacteria by impairing phagosome maturation and lysosomal interaction (Heckmann et al., 2017; Heckmann and Green, 2019; Martinez et al., 2011; Martinez et al., 2016; Martinez et al., 2015).”
InfluentialSelf-citationRetractedMartinez, J., Almendinger, J., Oberst, A., Ness, R., Dillon, C. P., Fitzgerald, P., Hengartner, M. O., & Green, D. R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113421108 · Cited by 655 · cited 3×
“2B) as measured by flow cytometry and described previously (Eng et al., 2010; He et al., 2009; Martinez et al., 2011; Martinez et al., 2015).”
Self-citationRetractedMartinez, J., Cunha, L. D., Park, S., Yang, M., Lu, Q., Orchard, R., Li, Q.-Z., Yan, M., Janke, L., Guy, C., et al. (2016) · Nature · doi:10.1038/nature17950 · Cited by 381 · cited 3×
“Since we have previously shown a vital role for LAP in regulating inflammatory immune responses (Martinez et al., 2016), we hypothesized that defective LANDO may have a similar effect.”
Self-citationRetractedOakley, H., Cole, S. L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.1202-06.2006 · Cited by 3,530 · cited 1×
“Cg-Tg (APPSwFILon, PSEN1 *M146L*L286V) 6799Vas) model (Oakley et al., 2006).”
Rubinsztein, D. C., Mariño, G., & Kroemer, G. (2011) · Cell · doi:10.1016/j.cell.2011.07.030 · Cited by 2,107 · cited 2×
“Roles for autophagy have been explored in the context of neuronal function, homeostasis, and alterations leading to disease pathology and neuronal dysfunction (Colacurcio et al., 2018; Ejlerskov et al., 2019; Harris and Rubinsztein, 2011; Menzies et al., 2017; Rubinsztein et al., 2015).”
Molecular Mechanisms That Influence the Macrophage M1–M2 Polarization Balance
Wang, N., Liang, H., & Zen, K. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00614 · Cited by 2,086 · cited 1×
“Microglia can undergo pro-inflammatory, classical (M1) or anti-inflammatory, alternative (M2) activation depending on which immune receptor is engaged, resulting in the activation of multiple downstream intracellular signaling pathways (Wang et al., 2014).”
New tools for studying microglia in the mouse and human CNS
Bennett, M. L., Bennett, F. C., Liddelow, S. A., Ajami, B., Zamanian, J. L., Fernhoff, N. B., Mulinyawe, S. B., Bohlen, C. J., Adil, A., Tucker, A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1525528113 · Cited by 1,804 · cited 1×
“We observed that over 90% of CD11b+ cells in brains from the 5xFAD Rubicon+/− and−/− mice were TMEM119+ (a microglia-specific marker (Bennett et al., 2016)) (Fig.”
TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
Wang, Y., Cella, M., Mallinson, K., Ulrich, J. D., Young, K. L., Robinette, M. L., Gilfillan, S., Krishnan, G. M., Sudhakar, S., Zinselmeyer, B. H., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
α-Synuclein Is Degraded by Both Autophagy and the Proteasome
Webb, J. L., Ravikumar, B., Atkins, J., Skepper, J. N., & Rubinsztein, D. C. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300227200 · Cited by 1,429 · cited 1×
“…in neurons, most likely by the canonical autophagic process of aggrephagy (Frake et al., 2015; Menzies et al., 2017; Qaisiya et al., 2017; Sarkar et al., 2007; Sarkar et al., 2009; Webb et al., 2003; Yamamoto and Simonsen, 2011), effects in microglia of the CNS are more likely due to LANDO.”
LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation
Kabeya, Y., Mizushima, N., Yamamoto, A., Oshitani-Okamoto, S., Ohsumi, Y., & Yoshimori, T. (2004) · Journal of Cell Science · doi:10.1242/jcs.01131 · Cited by 1,394 · cited 4×
“The requirement for ATG4, which converts LC3 to LC3-I (Kabeya et al., 2004) and the effect of RavZ, which irreversibly cleaves lipidated LC3 (Choy et al.”
Influential
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1 of the 90 references couldn’t be matched to a known paper.
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Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
“Microglia appear to clear Aβ through a process termed LC3-associated endocytosis (LANDO) that also recycles Aβ receptors (CD36, TREM2, TLR4) back to the cell surface; if this is genetically deleted in 5xFAD mice, there is increased Aβ accumulation, microgliosis with release of proinflammatory cytokines, tau hyperphosp…”
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,897
Self-citationMicroglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
Autophagy in major human diseases
Klionsky, D. J., Petroni, G., Amaravadi, R. K., Baehrecke, E. H., Ballabio, A., Boya, P., Bravo‐San Pedro, J. M., Cadwell, K., Cecconi, F., Choi, A. M. K., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2021108863 · Cited by 1,585
Self-citationAutophagy and autophagy-related pathways in cancer
Debnath, J., Gammoh, N., & Ryan, K. M. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00585-z · Cited by 1,506
Metadata
- Authors
- Heckmann, B. L., Teubner, B. J. W., Tummers, B., Boada-Romero, E., Harris, L., Yang, M., Guy, C. S., Zakharenko, S. S., & Green, D. R.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Green, Douglas R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-07
- Volume
- 178
- Issue
- 3
- Pages
- 536-551.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6689199
- OpenAlex
- W2953948138
- Semantic Scholar
- f14bdb656ef7b729cf199d36d42394767974c4eb
- Cited by
- 503
- References
- 90
- Citations by year
- 2026: 42 · 2025: 77 · 2024: 73 · 2023: 71 · 2022: 82 · 2021: 76 · 2020: 65 · 2019: 16
- FWCI
- 40.96
- Type
- journal article
- Language
- en
- Update notices
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Lupus Research Alliance
- American Lebanese Syrian Associated Charities
- National Institutes of Health (AI138492, AI40646, CA231423, CA231620)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Lando, Alzheimer's disease, amyloid-beta clearance, microglia, autophagy, neuroinflammation, reactive microgliosis, tau hyperphosphorylation, neurodegeneration, memory impairment, inflammatory cytokines
- MeSH terms
- RAW 264.7 Cells, Autophagy-Related Proteins, Autophagy-Related Protein 5, Alzheimer Disease, Animals, Disease Models, Animal, Endocytosis, Hippocampus, Membrane Glycoproteins, Mice, Transgenic, Microtubule-Associated Proteins, Receptors, Immunologic, Cytokines, Amyloid beta-Peptides, Microglia, CD36 Antigens, Intracellular Signaling Peptides and Proteins, Toll-Like Receptor 4, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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Statistics and arithmetic are recomputed, not judged.
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