The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index; 7 of the 9 sources its claims cite were checked for support.
LRP1 is a master regulator of tau uptake and spread
Open accessAbstract
The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies-including Alzheimer's disease, frontotemporal dementia and chronic traumatic encephalopathy 1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity 2. This observation and complementary experimental studies 3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.
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Claims the paper makes
33 Own result · 6 Supported · 6 Own interpretation · 5 Own method · 1 Partly supported · 1 No full text of the sources · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“Point mutations of key residues in RAP needed for its interaction with LRP110 (K256A, K270A – “mtRAP”) were sufficient to reduce this competitive effect (Extended Data Fig. 2a,b).”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Supportedcites [10] Dolmer, K., Campos, A. & Gettins, P. G. Quantitative dissection of the binding contributions of ligand lysines of the receptor-associated protein (RAP) to the low density lipoprotein receptor-related protein (LRP1). J. Biol. Chem. 288, 24081–24090 (2013). source
The citation is attached to the identification of K256 and K270 as important for RAP–LRP1 interaction, not to the citing authors’ tau-uptake result. The source’s binding-study passage says these two residues together account for 83% of the interaction energy, and its introductory passage reports reduced affinity for K256A and K270A mutations. The reduced competitive effect on tau uptake is attributed to the citing paper’s Extended Data, not to this source. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“A newly developed model of tau spread has been described recently that utilizes an adeno-associated virus (AAV) and allows reliable discrimination of neurons that have been transduced to express human tau (hTau) versus neurons that receive hTau protein through spread19.”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Supportedcites [19] Wegmann, S. et al. Experimental evidence for the age dependence of tau protein spread in the brain. Sci. Adv. 5, eaaw6404 (2019). source
The Results section, “Adeno-associated viruses to visualize tau protein spread between neurons,” explicitly says the AAV GFP-2a-huTau construct reliably distinguishes neurons expressing human tau from neurons receiving tau through protein spread. It identifies transduced neurons by GFP and huTau expression, and recipient neurons by huTau without GFP. (LLM, conf=0.95)
plain- Asserted: passes — The authors put it forward as true.
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- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Native LRP1 is highly expressed in neurons at the post-synaptic density17,18”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Not checked — no full text of the sourcecites [17] Andersen, O. M. & Willnow, T. E. Lipoprotein receptors in Alzheimer’s disease. Trends Neurosci. 29, 687–694 (2006). source
- Partly supportedcites [18] Nakajima, C. et al. Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes. J. Biol. Chem. 288, 21909–21923 (2013). sourceExperimental — accuracy not yet measured
The Subcellular Localization of LRP1 in Neurons section (Fig. 2; page not provided) reports LRP1 in neuronal postsynaptic-density fractions. It also describes LRP1 at other neuronal locations and says only a fraction is in or near synapses, so it does not establish that LRP1 is highly expressed at the postsynaptic density. (LLM, conf=0.88)
plain- Asserted: passes — The authors put it forward as true.
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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
“Only mLRP4 improved K18 uptake (Fig. 2e)”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“Further, mLRP4 was able to co-immunoprecipitate tau confirming an interaction between the two (Extended Data Fig. 2d).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
“whereas spread was greatly diminished in LRP1 knockdown animals (19 ± 19 hTau+/GFP- cells/mm2) (Fig. 4d).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Tau spread in vivo is likely mediated trans-synaptically.
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
“Microscopy of adherent iPSNs showed that LRP1 knockdown efficiently reduced the amount of internalized tau (Tau-488; green; Fig. 3a).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“but did not influence the internalization of transferrin (Fig. 2a)”
§ LRP1 is a master regulator of tau uptake and spread > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“yet failed to reduce transferrin uptake (Extended Data Fig. 2g)”
§ LRP1 is a master regulator of tau uptake and spread > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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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
“Results showed that incubation of H4 cells in ApoE conditioned medium significantly reduced uptake of full-length tau”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Probably not a substantial claim. 8
- It may state two separate claims as one. 12
Every source the paper cites for this claim was checked and supports it.
In the paper
“However, HSPGs are known to act both independently and in concert with co-receptors to mediate endocytosis26.”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Supportedcites [26] Christianson, H. C. & Belting, M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol. 35, 51–55 (2014). source
Section 2.1 states that HSPG can act as an independent internalizing receptor. Section 2.2 describes HSPG/co-receptor clustering during uptake, supporting the claim that HSPGs can also act in concert with co-receptors. (LLM, conf=0.92)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“ApoE4 is known to have the lowest levels of circulating protein in the brain25, suggesting it would be the least effective in inhibiting tau-LRP1 interactions and, thus, suppressing tau spread.”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Supportedcites [25] Mahley, R. W. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 36, 1305–1315 (2016). source
The section “ApoE4 Structure Targets It for Degradation and Decreased Lipid Transport” states that apoE4 is present at lower levels in the CNS and CSF; the neuropathology section specifies lower levels relative to apoE3/2. The citation is attached to that level claim, while the proposed effect on tau-LRP1 interactions and tau spread is the citing authors’ inference. (LLM, conf=0.92)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“LRP1 is highly expressed in neurons, but it has also been shown that LRP1 is present in other cell types including astrocytes and microglia21.”
§ LRP1 is a master regulator of tau uptake and spread > Results
What the sources say
- Supportedcites [21] Auderset, L., Cullen, C. L. & Young, K. M. Low density lipoprotein-receptor related protein 1 is differentially expressed by neuronal and glial populations in the developing and mature mouse central nervous system. PLoS ONE 11, e0155878 (2016). source
The Conclusions state that LRP1 is expressed by both microglia and astrocytes in the developing and mature mouse CNS. This directly supports the cited claim that LRP1 is present in those cell types. (LLM, conf=0.94)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“This engineered capsid allows efficient transduction of the central nervous system via the vasculature33.”
§ LRP1 is a master regulator of tau uptake and spread > Methods: > AAV Production and Purification
What the sources say
- Supportedcites [33] Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017). source
The Discussion reports that AAV-PHP.eB transduced the majority of neurons in the cortex and striatum at a low systemic dose. The Methods describe intravenous administration of the AAV vectors in adult mice, supporting the vascular route. The demonstrated result is in mice. (LLM, conf=0.91)
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Supported
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
“Similarly, to H4 cells, LRP1 knockdown or the addition of RAP had no effect on transferrin uptake in iPSNs (Fig. 3c).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It 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
“and reduced but did not completely inhibit the uptake of sonicated tau fibrils (Fig. 1c)”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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 examined the uptake of the N-terminus of tau (amino acids 1–243) and found that both mLRP4 and to a lesser extent, mLRP2 could rescue N-terminal uptake (Fig. 2f).”
§ LRP1 is a master regulator of tau uptake and spread > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It 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
“Quantification of tau endocytosis by flow cytometry confirmed the reduction of tau uptake upon LRP1 knockdown or upon addition of RAP, but not mtRAP into the culture medium (Fig. 3b,c).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“Uptake of a disease-relevant mutant of tau and of phosphorylated tau were also affected by LRP1 knockdown (Extended Data Fig. 1d).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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 no effect of sex on the spread phenotype (Extended Data Fig. 3c).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably 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
“Tau spread was also observed in the contralateral hippocampus in PBS and scramble injected mice, but was absent in our LRP1 shRNA animals (Fig. 4j).”
§ LRP1 is a master regulator of tau uptake and spread > Results
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: Tau spread in vivo is likely mediated trans-synaptically.
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 also noted that while LRP1 knockdown was sufficient to reduce uptake of the N-terminus, we did not observe the striking inhibition observed with constructs containing the microtubule binding repeat region.”
§ LRP1 is a master regulator of tau uptake and spread > Results
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“This suggests a model where a primary interaction site on mLRP4 mediates tau uptake, but that the N-terminus of tau can also mediate interactions with a secondary site on mLRP2.”
§ LRP1 is a master regulator of tau uptake and spread > Results
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“sample sizes were based on previously published work and chosen to support meaningful conclusions”
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Animals
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. 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
“and no specific method of randomization was used.”
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably 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
“Here we show that the low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) controls tau endocytosis and subsequent spread.”
§ LRP1 is a master regulator of tau uptake and spread > Abstract
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The cellular mechanisms underlying tau propagation remain poorly understood.
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
“No calculations were performed to predetermine sample size”
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Animals
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“Animal mosaics were quantified under blinding conditions, file names were withheld until after image analysis was completed.”
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Large-scale mosaic acquisition and image registration
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The cellular mechanisms underlying tau propagation remain poorly understood.
“However, while tau propagation has been extensively studied, the underlying cellular mechanisms remain poorly understood.”
The paper relies on this without support.
Tau spread in vivo is likely mediated trans-synaptically.
“previous work has highlighted that spread of tau in vivo is likely mediated trans-synaptically.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Studies indicate that APOE binding is integral to some of these processes [16–20] with differences in APOE isoform-specific receptor binding affinity and lipid interactions affecting neuroinflammation, tau pathology, and amyloid plaque dynamics [21–24].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Collectively, these recent findings underscore the influence of APOE and APOE3Ch on both Aβ and tau pathology, either directly or through downstream effects such as neuroinflammation.”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [20]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Mammalian expression systems retain physiologically relevant secretory, folding and post-translational modification mechanisms, but column-purified recombinant ApoE is invariably prepared as apoprotein.22–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [24]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“it has been observed that ApoE in general reduces LRP1-mediated tau uptake by neurons and propagation [52]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [52]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“The other primary apoE metabolic receptor, LRP1, has been shown to mediate tau uptake in vitro and drastically increase the propagation of the P301L human tau protein expressed by an AAV virus in vivo (Rauch et al., 2020)”
From Overexpressing low‐density lipoprotein receptor reduces tau‐associated neurodegeneration in relation to apoE‐linked mechanisms (2021) · cites this paper as Rauch et al., 2020
The cited source says what the claim attributes to it.
In the citing paper
“LRP1 mediates tau endocytosis and promotes tau propagation between neurons”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Rauch et al 2020
The cited source says what the claim attributes to it.
In the citing paper
“LRP1 also mediates tau uptake by neurons, being involved in tau spreading.”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“which is possibly related to the potentiation of tau pathology throw enhanced LRP-1 mediated tau propagation [52]”
From Apoe4 and Alzheimer’s Disease Pathogenesis—Mitochondrial Deregulation and Targeted Therapeutic Strategies (2023) · cites this paper as [52]
The cited source says what the claim attributes to it.
In the citing paper
“However, unlike tau fibrils [29], LRP1-KO only had a mild inhibitory effect on the uptake of α-Syn PFFs (~ 5–10% reduction) (Fig. 2h).”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“Tau interacts with LRP1 through lysine residues in the microtubule-binding repeat region [29].”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [29]
The cited source says what the claim attributes to it.
In the citing paper
“and TAU spreading in mouse brain is mainly mediated by LRP1 (52).”
From LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation (2023) · cites this paper as [52]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Mammalian expression systems retain physiologically relevant secretory, folding and post-translational modification mechanisms, but column-purified recombinant ApoE is invariably prepared as apoprotein.22–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [24]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Although ApoE is not detected in appreciable quantities in its apo form in physiological fluids, to date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.21–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [24]
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Although ApoE is not detected in appreciable quantities in its apo form in physiological fluids, to date all reports describing the biochemical properties of this recombinant protein have deployed lipid-free biosynthetic materials.21–25”
From ApoE is Secreted as a Lipid Nanoparticle by Mammalian Cells: Implications for Alzheimer’s Disease Pathogenesis (2025) · cites this paper as [24]
Experimental — accuracy not yet measuredIn the citing paper
“Such screens provide rich information on cellular processes such as differentiation72, immune responses72,73,75, stress responses74 and compensatory responses76 and enable high-throughput mapping of regulatory elements77.”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [72]
In the citing paper
“While screens based on survival or FACS monitor low-dimensional phenotypes, pooled CRISPR screens can also be coupled to single-cell RNA sequencing to provide high-dimensional readouts of the effects of gene perturbation72–75”
From CRISPR-based functional genomics for neurological disease (2020) · cites this paper as [72]
In the citing paper
“A recent study showed that the low-density lipoprotein receptor-related protein 1 (LRP1) expressed in neurons regulates the endocytosis of tau and its subsequent spread [74].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [74]
In the citing paper
“Knockdown or inhibition of LRP1 significantly reduces tau uptake and spread in vitro and in vivo [74].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [74]
In the citing paper
“For example, the multifunctional receptor LRP1 appears to be a primary mechanism subverting uptake of soluble extracellular tau (58, 59), so that it can at least partly escape degradation and be released to the cytoplasm.”
From All the Tau We Cannot See (2023) · cites this paper as [59]
In the citing paper
“Among these distinct mechanisms, the LRP1-mediated cellular uptake and spread is shown as a common mechanism for the cell-to-cell transmission of both tau [29, 42] and α-Syn (from this study).”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [29]
In the citing paper
“A recent study also identified LRP1 as a key regulator for the uptake and spread of microtubule-associated protein tau [29].”
From LRP1 is a neuronal receptor for α-synuclein uptake and spread (2022) · cites this paper as [29]
In the citing paper
“LRP1 is known to bind and mediate uptake of oligomeric TAU into cells, and this is fully blocked by LRPAP1 with an inhibition constant (Ki) of 5 nM extracellular LRPAP1 (52)”
From LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation (2023) · cites this paper as [52]
In the citing paper
“LRP1 and related receptors of the LDL receptor family are known to mediate endocytosis or phagocytosis of a wide range of extracellular targets, including Aβ, TAU, ApoE and apoptotic cells, via ligand binding to these receptors (6, 28, 52).”
From LRPAP1 is released from activated microglia and inhibits microglial phagocytosis and amyloid beta aggregation (2023) · cites this paper as [52]
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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Cell Culture
“Knockdown was confirmed with qPCR and western blot analysis using anti-LRP1 (Sigma L2295; 1:1000) and anti-actin (Sigma A5441; 1:10000) as a loading control (Extended Data Fig. 1b,d).”
§ LRP1 is a master regulator of tau uptake and spread > Extended Data
“e, Western blot analysis of LRP1 in WT, NT sgRNA or LRP1 sgRNA H4i cells.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ LRP1 is a master regulator of tau uptake and spread > Results
“While not a focus of this work, we did observe instances of hTau+ astrocytes (Extended Data Fig. 3e) that will be a topic of future studies.”
§ LRP1 is a master regulator of tau uptake and spread > Extended Data
“d, Immunohistochemistry of hTau+ astrocytes in PBS injected animal (green, Sox2; red, hTau; blue, Hoechst; scale bar 20μm, n=3).”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ LRP1 is a master regulator of tau uptake and spread > Methods: > Statistical Analysis
“For qPCR data unpaired t-tests were used to determine significance.”
§ LRP1 is a master regulator of tau uptake and spread > Extended Data
“All results in b-e were performed in three independent experiments and normalized to WT uptake (100%). Data is expressed as mean ± s.d. One-way ANOVA with Tukey’s method, two-sided was performed to determine significance, ****=p-value < 0.0001.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ LRP1 is a master regulator of tau uptake and spread > Results
“Animals expressing LRP1 shRNA showed reduced expression for LRP1 as determined by qPCR and IHC (Extended Data Fig. 3b,f).”
§ LRP1 is a master regulator of tau uptake and spread > Extended Data
“e, Immunohistochemistry of scramble shRNA and LRP1 shRNA animals (green, LRP1; blue; Hoechst, scale bar 20μm, n=3).”
Citations
Cites
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
Cryo-EM structures of tau filaments from Alzheimer’s disease
Fitzpatrick, A. W. P., Falcon, B., He, S., Murzin, A. G., Murshudov, G., Garringer, H. J., Crowther, R. A., Ghetti, B., Goedert, M., & Scheres, S. H. W. (2017) · Nature · doi:10.1038/nature23002 · Cited by 2,061
Chan, K. Y., Jang, M. J., Yoo, B. B., Greenbaum, A., Ravi, N., Wu, W.-L., Sánchez-Guardado, L., Lois, C., Mazmanian, S. K., Deverman, B. E., et al. (2017) · Nature Neuroscience · doi:10.1038/nn.4593 · Cited by 1,578
Self-citationPropagation of Tau Pathology in a Model of Early Alzheimer's Disease
de Calignon, A., Polydoro, M., Suárez-Calvet, M., William, C., Adamowicz, D. H., Kopeikina, K. J., Pitstick, R., Sahara, N., Ashe, K. H., Carlson, G. A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2011.11.033 · Cited by 1,427
Self-citationApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Initiative, A. D. N., Shi, Y., Yamada, K., Liddelow, S. A., Smith, S. T., Zhao, L., Luo, W., Tsai, R. M., Spina, S., Grinberg, L. T., et al. (2017) · Nature · doi:10.1038/nature24016 · Cited by 1,220
Szymczak, A. L., Workman, C. J., Wang, Y., Vignali, K. M., Dilioglou, S., Vanin, E. F., & Vignali, D. A. A. (2004) · Nature Biotechnology · doi:10.1038/nbt957 · Cited by 1,059
Horlbeck, M. A., Gilbert, L. A., Villalta, J. E., Adamson, B., Pak, R. A., Chen, Y., Fields, A. P., Park, C. Y., Corn, J. E., Kampmann, M., et al. (2016) · eLife · doi:10.7554/elife.19760 · Cited by 894
Self-citationHeparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds
Holmes, B. B., DeVos, S. L., Kfoury, N., Li, M., Jacks, R., Yanamandra, K., Ouidja, M. O., Brodsky, F. M., Marasa, J., Bagchi, D. P., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1301440110 · Cited by 859
Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules
Falcon, B., Zivanov, J., Zhang, W., Murzin, A. G., Garringer, H. J., Vidal, R., Crowther, R. A., Newell, K. L., Ghetti, B. F., Goedert, M., et al. (2019) · Nature · doi:10.1038/s41586-019-1026-5 · Cited by 722
Lillis, A. P., Van Duyn, L. B., Murphy-Ullrich, J. E., & Strickland, D. K. (2008) · Physiological Reviews · doi:10.1152/physrev.00033.2007 · Cited by 669
Cited by
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Knopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606
Self-citationSynergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242
Self-citationAPOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Self-citationApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies
Raulin, A.-C., Doss, S. V., Trottier, Z. A., Ikezu, T. C., Bu, G., & Liu, C.-C. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00574-4 · Cited by 756
Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Domínguez, L., Shea, J., Dokholyan, N. V., Simone, A. D., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 680
Metadata
- Authors
- Rauch, J. N., Luna, G., Guzman, E., Audouard, M., Challis, C., Sibih, Y. E., Leshuk, C., Hernandez, I., Wegmann, S., Hyman, B. T., Gradinaru, V., Kampmann, M., & Kosik, K. S.
- Affiliations
- University of California, Santa Barbara (US)
- California Institute of Technology (US)
- German Center for Neurodegenerative Diseases (DE)
- Harvard University (US)
- QB3 (US)
- Corresponding author
- Kosik, Kenneth S.
- ORCID
- Venue
- Nature
- Published
- 2020-04-01
- Volume
- 580
- Issue
- 7803
- Pages
- 381-385
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7687380
- OpenAlex
- W3014222043
- Semantic Scholar
- 334a235cd1b3178785f141ef3d51deb120ae3bc8
- Cited by
- 541
- References
- 34
- Citations by year
- 2026: 58 · 2025: 85 · 2024: 93 · 2023: 90 · 2022: 73 · 2021: 85 · 2020: 57
- FWCI
- 45.85
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DZNE Pub (submittedVersion)
- Funders
- Larry L. Hillblom Foundation
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Edward N. and Della L. Thome Memorial Foundation
- Deutsches Zentrum für Neurodegenerative Erkrankungen
- National Institutes of Health (1r56ag057528-01a1)
- University of California, Santa Barbara
- National Institute on Aging (R56AG062479, R01AG023100, R56 AG057528, RF1AG059789, K99AG064116, R01AG062359, P30AG062421)
- National Institute of General Medical Sciences (DP2GM119139)
- National Institute of Neurological Disorders and Stroke (U54NS100717)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- LRP1, tau protein, tau spread, tauopathy, Alzheimer's disease, frontotemporal dementia, chronic traumatic encephalopathy, prion-like propagation, endocytosis, lysine residues, microtubule-binding repeats, neurodegeneration, iPSC-derived neurons
- MeSH terms
- Animals, Cell Line, Endocytosis, Female, Humans, Ligands, Male, Neurons, tau Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Mice
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