The DOI matches its Crossref record; 95 of the 97 references it cites were found in a registry or an index; 6 of the 34 sources its claims cite were checked for support.
Internalization of β-Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E
Open accessAbstract
Extracellular accumulation of beta-amyloid peptide (Abeta) has been linked to the development of Alzheimer disease. The importance of intraneuronal Abeta has been recognized more recently. Although considerable evidence indicates that extracellular Abeta contributes to the intracellular pool of Abeta, the mechanisms involved in Abeta uptake by neurons are poorly understood. We examined the molecular mechanisms involved in Abeta-(1-42) internalization by primary neurons in the absence of apolipoprotein E. We demonstrated that Abeta-(1-42) is more efficiently internalized by axons than by cell bodies of sympathetic neurons, suggesting that Abeta-(1-42) uptake might be mediated by proteins enriched in the axons. Although the acetylcholine receptor alpha7nAChR, previously suggested to be involved in Abeta internalization, is enriched in axons, our results indicate that it does not mediate Abeta-(1-42) internalization. Moreover, receptors of the low density lipoprotein receptor family are not essential for Abeta-(1-42) uptake in the absence of apolipoprotein E because receptor-associated protein had no effect on Abeta uptake. By expressing the inactive dynamin mutant dynK44A and the clathrin hub we found that Abeta-(1-42) internalization is independent of clathrin but dependent on dynamin, which suggests an endocytic pathway involving caveolae/lipid rafts. Confocal microscopy studies showing that Abeta did not co-localize with the early endosome marker EEA1 further support a clathrin-independent mechanism. The lack of co-localization of Abeta with caveolin in intracellular vesicles and the normal uptake of Abeta by neurons that do not express caveolin indicate that Abeta does not require caveolin either. Instead partial co-localization of Abeta-(1-42) with cholera toxin subunit B and sensitivity to reduction of cellular cholesterol and sphingolipid levels suggest a caveolae-independent, raft-mediated mechanism. Understanding the molecular events involved in neuronal Abeta internalization might identify potential therapeutic targets for Alzheimer disease.
Overview
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Written from the paper’s full text.
TL;DR
In primary neurons and in the absence of apolipoprotein E, β-amyloid peptide Aβ-(1-42) is internalized preferentially through distal axons and retrogradely transported to cell bodies. Uptake requires dynamin and cellular cholesterol/sphingolipids but is independent of clathrin, caveolin, α7nAChR, and LDL receptor family members, suggesting a caveolae-independent, raft-mediated endocytic pathway.
Key findings
- Aβ-(1-42) was internalized more efficiently by axons than by cell bodies; when added to distal axons, it was retrogradely transported to cell bodies, whereas anterograde transport from cell bodies was almost negligible.
- α7nAChR did not mediate uptake: 5 μM Aβ-(1-42) did not significantly compete with ¹²⁵I-α-bungarotoxin binding, and 10 μM α-bungarotoxin did not decrease fluo-Aβ-(1-42) internalization.
- LDL receptor family members were not required in the absence of apoE: 1 μM receptor-associated protein (RAP) did not inhibit Aβ uptake, although it dramatically decreased DiI-LDL internalization.
- Aβ uptake was dynamin-dependent but clathrin-independent: dynamin K44A reduced internalization/transport, whereas clathrin hub overexpression did not significantly affect Aβ uptake but blocked LDL internalization.
- Internalized Aβ did not co-localize with EEA1 or caveolin; caveolin-1 knockout neurons internalized Aβ as effectively as controls. Aβ partially co-localized with cholera toxin subunit B, and combined fumonisin B1 plus pravastatin reduced Aβ internalization by ~51%.
Methods
- Primary rat sympathetic neurons were cultured in three-compartment dishes to separate distal axons from cell bodies/proximal axons; rat basal forebrain cholinergic neurons and sympathetic neurons from caveolin-1 knockout and control mice were also used.
- Aβ-(1-42) preparations contained monomers and oligomers but no fibrils; internalization was assessed by fluorescence/confocal microscopy, biotinylated Aβ cleavage assays, ELISA, immunoblotting, and radioligand binding.
- Mechanistic tests used adenoviral expression of wild-type dynamin, dynamin K44A, and clathrin hub; RAP and α-bungarotoxin; and fumonisin B1 and pravastatin to reduce sphingolipid and cholesterol levels.
Limitations
- The paper states that the compartmentalized system does not permit exclusive study of dendrite uptake because the center compartment also contains cell bodies and proximal axons.
- The paper states that Aβ mass could not be quantified when Aβ was provided to cell bodies because surface-associated Aβ interfered with the determination.
- Evident from the text: findings are from cultured primary neurons under serum-free, apoE/lipoprotein-absent conditions, so relevance to in vivo Aβ uptake and apoE-containing environments is not directly established; several experiments were repeated only two or three times.
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Claims the paper makes
32 Own result · 18 Own interpretation · 14 No full text of the sources · 9 Own method · 4 No basis given · 3 Partly supported · 2 Supported · 2 Not checked yet · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“RAP, at a concentration that has been proven to inhibit ligand interaction of all LDLr family members (40), was unable to inhibit fluo-A-(1-42) uptake and transport (Fig. 2D).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
What the sources say
- Partly supportedcites [40] LaDu, 2000, J. Biol. Chem. sourceExperimental — accuracy not yet measured
In “RAP Blocks Aβ-induced Activation and Changes in apoE but Not apoJ” (page unavailable), the paper says a high RAP concentration was chosen to inhibit LRP and LDLR, the two primary LDLR-family members expressed by the astrocytes studied. It does not establish that this concentration inhibits ligand interactions with all LDLR-family members. The uptake-and-transport result is attributed to the citing paper’s own Fig. 2D, not to this source. (LLM, conf=0.85)
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.
- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Both increased intracellular A generation and uptake of extracellular A are consistent with the endosomal/ lysosomal localization of intracellular A (12,13).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Supportedcites [12] Takahashi, 2002, Am. J. Pathol. source
The Discussion reports that Aβ42 can be internalized by neurons and suggests that MVB-associated Aβ42 may derive from uptake at the plasma membrane; it also discusses internally generated Aβ. Another Discussion passage identifies MVBs as part of the endosomal/lysosomal system and reports Aβ42 accumulation there. Page numbers are not provided in our copy. (LLM, conf=0.91)
- Not checked — no full text of the sourcecites [13] Shie, 2003, Neuroreport source
plaincorrelational- 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.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The observation that cortical neurons that accumulate A-(1-42) in brains of Down syndrome patients are apoptotic (7,8) provided additional indications of the importance of intracellular A (7,8).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Not checked — no full text of the sourcecites [7] Busciglio, 2002, Neuron source
- Partly supportedcites [8] Helguera, 2005, J. Neurosci. sourceExperimental — accuracy not yet measured
In the section on ets-2 expression in DS and AD brains (page not available), the paper reports intracellular Aβ in neurons from Down syndrome/Alzheimer’s disease brains and separately associates ets-2 expression with the apoptosis marker bax. Figure 7 shows Aβ42 and ets-2 in one neuron, and bax and ets-2 in another; it does not establish that the Aβ42-accumulating neurons were themselves apoptotic. (LLM, conf=0.86)
hedgedcorrelational- 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.
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
“Inhibition of SPL synthesis or cholesterol alone did not decrease A internalization (Fig. 6, B (f and j versus b) and C).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
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.
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
“Inhibition of SPL synthesis or cholesterol alone did not decrease A internalization (Fig. 6, B (f and j versus b) and C).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
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.
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
“overexpression of clathrin hub did not significantly affect A internalization (Fig. 3, n versus b).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
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.
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, Fumonisin B1 and pravastatin together caused significant reduction (ϳ51%) in A internalization (Fig. 6, B (n versus b) and C).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
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
“We demonstrated that A-(1-42) is more efficiently internalized by axons than by cell bodies of sympathetic neurons”
- Also stated in: § A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We · plain
“The fact that A internalization occurs preferentially through axons”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
boosteddirect- 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.
- Also stated in: § A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We · 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
“Importantly we found a dramatic enrichment of this receptor in distal axons compared with cell bodies/proximal axons”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
boostedcorrelational- 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
“Although pravastatin treatment caused a significant decrease in total cholesterol mass, which was similar to that obtained with methyl--cyclodextrin (Fig. 6D)”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
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. 19
- It may state two separate claims as one. 14
Every source the paper cites for this claim was checked and supports it.
In the paper
“Besides, in the triple transgenic mouse model for AD there is a correlation between long term potentiation abnormalities and intraneuronal A accumulation, all of which take place before the appearance of plaques or tangles (10).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Supportedcites [10] Oddo, 2003, Neuron source
The Abstract states that long-term synaptic plasticity deficits correlate with intraneuronal Aβ accumulation in 3×Tg-AD mice, and that LTP deficits appear before plaque and tangle pathology. The Discussion likewise says that synaptic transmission and LTP deficits precede overt plaque and tangle formation. (LLM, conf=0.94)
plaincorrelational- 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. It may state two separate claims as one.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The amyloid cascade hypothesis predicts that a gradual increase of A-(1-42) levels in brain interstitial fluid (3,4) may lead to A oligomerization and eventually to A fibrillization (5).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Partly supportedcites [3] Skovronsky, 1998, J. Cell Biol. sourceExperimental — accuracy not yet measured
The citation to this paper is attached to the proposed progression toward fibrillization, not specifically to the preceding claim about brain interstitial fluid. The Discussion says concentrated intracellular Aβ1-42 could nucleate fibril formation, but it does not describe an intervening oligomerization step; its proposed route is intracellular. (LLM, conf=0.86)
- Not checked — no full text of the sourcecites [4] Walsh, 2000, Biochemistry source
- Not checked — no full text of the sourcecites [5] Selkoe, 2004, Ann. Intern. Med. source
hedgedconditional- 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.
- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“Furthermore, microinjection of A-(1-42) or cDNA encoding A-(1-42) in cultured human neurons resulted in neurotoxicity (9).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Supportedcites [9] Zhang, 2002, J. Cell Biol. source
The Results section reports that microinjected Aβ1–42 caused significant death in primary cultured human neurons. It also reports that microinjected cDNA expressing cytosolic Aβ1–42 was toxic to those neurons. (LLM, conf=0.94)
plaindirect- 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.
- 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
“By confocal studies we demonstrated, however, that A does not co-localize with caveolin but partially co-localizes with CTxB, suggesting that A-(1-42) internalization involves non-caveolae, GM1-containing rafts.”
- Also stated in: § DISCUSSION · plain
“Internalized A-(1-42) partially co-localizes with cholera toxin subunit B.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
plaincorrelational- 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.
- Also stated in: § DISCUSSION · 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
“In addition, we found that there is robust retrograde transport of A to cell bodies, but the anterograde transport from cell bodies to axons was negligible.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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.
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 demonstrated that A-(1-42) is preferentially internalized through distal axons and retrogradely transported to cell bodies.”
- Also stated in: § DISCUSSION · plain
“A-(1-42) is internalized preferentially by axons.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
boosteddirect- 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.
- Also stated in: § DISCUSSION · 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
“We demonstrated that reduction of cellular cholesterol or sphingolipids levels alone is not sufficient to block A internalization, but the simultaneous decrease in cholesterol and sphingolipids effectively reduced A uptake and trafficking.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
boosteddirect- 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.
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
“Data are representative of two independent experiments with similar results.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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. It may state two separate claims as one.
In the paper
“A is a 39 -43-amino acid peptide derived from the proteolytic cleavage of the amyloid precursor protein (APP) (2).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Not checked — no full text of the sourcecites [2] Selkoe, 1999, Nature source
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.
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 turn A binding to apoE is regulated by the apoE isoform present.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
plaindirect- 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: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. 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
“The proportion of each pool of A will be determined by the levels of A in the extracellular space and by the efficiency of A binding to apoE.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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: unclear — It is unclear why the paper says it holds.
It may state two separate claims as one.
In the paper
“Intracellular accumulation of A-(1-42) results from one or a combination of the following processes: decreased A degradation (disruption of the ubiquitin-proteasome system), increased intracellular generation of A, and increased uptake of A from an external source (11).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Not checked — no full text of the sourcecites [11] D'Andrea, 2002, Neurosci. Lett. source
plaindirect- 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. It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“On the other hand, very little information is available on the role of cholesterol in A internalization.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check 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. It may be too vague to check against evidence.
In the paper
“The use of the three-compartment culture system in our studies allowed us to directly examine A uptake by axons because neurons are plated in the center compartment of the dish, which is over 1 mm wide; therefore neurites that grow in the side compartments represent axons exclusively (74).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites [74] Campenot, 1982, Dev. Biol. source
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.
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 experiments were performed three times with comparable results.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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 states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“None of these studies investigated the role of cholesterol in A internalization.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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.
Probably not a substantial claim.
In the paper
“All A preparations used were similar to those characterized previously (24) in that they contain monomers and oligomers of A but do not contain fibrils (see supplemental Fig. 1, A and B).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > EXPERIMENTAL PROCEDURES
What the sources say
- Not checked — no full text of the sourcecites [24] Dahlgren, 2002, J. Biol. Chem. source
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.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although the evidence supports the notion that endocytosis is involved in A internalization, the molecular details of A uptake were not addressed in those studies, and the precise A points of entry were not investigated.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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.
Probably not a substantial claim. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Previous studies have demonstrated internalization of synthetic A peptides in neurons of hippocampal slices (65,70) and in neuronal models in culture (65,(71)(72)(73).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
What the sources say
boosted- 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.
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
“Five hundred to 1000 neurons per treatment were counted by an observer”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Assessment of A Internalization by Enzyme-linked Immunosorbent Assay-A-(1-42
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
“Our experiments also indicated that independent reduction of cholesterol or sphingolipids results in decreased CTxB uptake demonstrating that the drug treatments were effective.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
boosteddirect- 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.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“To our knowledge the role of the LDLr family in the uptake of A in the absence of LDLr ligands has not been investigated.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
hedged- 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.
In the paper
“Current evidence indicates that intraneuronal accumulation of A is an early pathological biomarker for the onset of AD and may contribute to the cascade of neurodegenerative events (6).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Not checked — no full text of the sourcecites [6] D'Andrea, 2001, Histopathology source
hedgedconditional- 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. It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“findings that oligomeric A deposits are present preferentially on distal axons and synapses in Tg2576 mouse brain and in central nervous system-derived neuronal cells suggested that these structures are important sites of A entry (14,32).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
What the sources say
hedgedcorrelational- 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.
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 experiment was repeated twice with comparable results.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
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.
None of the sources cited for this claim have been checked yet.
In the paper
“Internalization of the complex A-apoE has been extensively studied (19 -21)”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
boosted- 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.
In the paper
“In brains of individuals with Alzheimer disease (AD), 2 -amyloid peptide (A) aggregates and accumulates as toxic fibrils in neuritic plaques and toxic soluble oligomers (1).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Abstract
What the sources say
- Not checked — no full text of the sourcecites [1] Selkoe, 2001, J. Alzheimer's Dis. source
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. It may state two separate claims as one.
The paper relies on this without support.
A pool of free Aβ likely exists.
“Besides a pool of free A likely exists.”
The paper relies on this without support.
This pool likely increases considerably during AD development.
“This pool likely increases considerably during AD development.”
The paper relies on this without support.
The mechanism that mediates uptake of Aβ not complexed to apoE is largely unknown.
“however, the mechanism that mediates uptake of A that is not complexed to apoE is largely unknown.”
The paper relies on this without support.
Direct demonstration of Aβ uptake by axons is still missing.
“Nevertheless to our knowledge direct demonstration of A uptake by axons is still missing.”
The paper relies on this without support.
Plasma membrane cholesterol and sphingolipid levels regulate raft-mediated endocytosis.
“Plasma membrane cholesterol and sphingolipid levels regulate raft-mediated 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?
The cited source doesn’t support the claim as written.
In the citing paper
“In contrast, evidence suggests that internalization of Ab not associated with ApoE occurs through nonendocytotic mechanisms, which are based on the translocation of the cell surface bound Ab directly to the cytosol and results in accumulation of Ab primarily outside the endosomal/lysosomal compartment.28,45,46”
From Blocking the Interaction between Apolipoprotein E and Aβ Reduces Intraneuronal Accumulation of Aβ and Inhibits Synaptic Degeneration (2013) · cites this paper as [45]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
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
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
“Sympathetic neurons were given fluo-A-(1-42) for 30 min, and the internalization compartments were analyzed by threecolor immunofluorescence to simultaneously detect EEA1 (a marker of early endosomes), caveolin (a marker of the caveolae pathway), and A-(1-42) (Fig. 4).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
“Rat neurons were incubated with fluo-A-(1-42) (5 M) for 1 h at 37 °C.”
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
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > Assessment of A Internalization by Immunofluorescence and Confocal Microscopy-Fluo-A-(1-42
“For detection of caveolin, primary rabbit anti-caveolin (1:250) and secondary Alexa594-labeled goat anti-rabbit antibody prepared in blocking buffer (1:1000) were used.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
“After fixation EEA1 and caveolin were detected using the primary antibodies indicated under "Experimental Procedures" followed by an Alexa647-conjugated anti-rabbit antibody and an Alexa594-conjugated anti-mouse antibody, respectively.”
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
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > EXPERIMENTAL PROCEDURES
“Binding experiments were performed four times, each in triplicate, and data are represented as percentage of specific binding.”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > DISCUSSION
“The data display specific binding in the presence of A for three separate experiments (Exp1-3) and the corresponding average (Av).”
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
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > EXPERIMENTAL PROCEDURES
“Displacement of 125 I- ␣-BTx binding sites was also simultaneously studied in the presence or absence of 100 M nicotine and 5 M A-(1-42).”
§ Internalization of -Amyloid Peptide by Primary Neurons in the Absence of Apolipoprotein E * □ S > A-(1-42) Is Preferentially Internalized by Axons, Is Retrogradely Transported, and Accumulates in Cell Bodies-We
“In contrast, 1 M unlabeled ␣-BTx (i.e.nonspecific binding) and 10 M nicotine potently displaced 125 I-␣-BTx binding”
Citations
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Research works printed but not linked: 2
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Correlation between Sialylation Status and Cell Susceptibility to Amyloid Toxicity
Sgambati, E., Tani, A., Leri, M., Delfino, G., Zecchi‐Orlandini, S., Bucciantini, M., & Nosi, D. (2022) · Cells · doi:10.3390/cells11040601 · Cited by 8
Picón-Pagès, P., Bosch-Morató, M., Subirana, L., Rubio-Moscardó, F., Guivernau, B., Fanlo-Ucar, H., Zeylan, M. E., Senyuz, S., Herrera-Fernández, V., Vicente, R., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24021278 · Cited by 6
Cholesterol and Fat Metabolism in Alzheimer’s Disease
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Metadata
- Authors
- Saavedra, L., Mohamed, A., Ma, V., Kar, S., & de Chaves, E. P.
- Affiliations
- University of Alberta (CA)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-12
- Volume
- 282
- Issue
- 49
- Pages
- 35722-35732
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2014341627
- Cited by
- 118
- References
- 97
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 6 · 2020: 2 · 2019: 3 · 2018: 6 · 2017: 4 · 2016: 6 · 2015: 1 · 2014: 8 · 2013: 6 · 2012: 17
- FWCI
- 8.87
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- University of Alberta
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- beta-amyloid peptide, amyloid-beta 42, apolipoprotein E deficiency, axons, sympathetic neurons, low-density lipoprotein receptor family, dynamin, clathrin-independent endocytosis, caveolae, lipid rafts, cholesterol, sphingolipids, Alzheimer's disease
- MeSH terms
- Adrenergic Fibers, Alzheimer Disease, Animals, Apolipoproteins E, Axons, Cells, Cultured, Cholera Toxin, Cholesterol, Clathrin, Endocytosis, Peptides, Receptors, Nicotinic, Sphingolipids, Amyloid beta-Peptides, Rats, Sprague-Dawley, Caveolae, Dynamins, Rats, alpha7 Nicotinic Acetylcholine Receptor
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 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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