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Aβ40 Inhibits Amyloid Deposition In Vivo
Open accessAbstract
Numerous studies have established a pivotal role for Aβ42 in Alzheimer's disease (AD) pathogenesis. In contrast, although Aβ40 is the predominant form of amyloid β (Aβ) produced and accumulates to a variable degree in the human AD brain, its role in AD pathogenesis has not been established. It has generally been assumed that an increase in Aβ40 would accelerate amyloid plaque formation in vivo. We have crossed BRI-Aβ40 mice that selectively express high levels of Aβ40 with both Tg2576 (APPswe, K670N+M671L) mice and BRI-Aβ42A mice expressing Aβ42 selectively and analyzed parenchymal and cerebrovascular Aβ deposition in the bitransgenic mice compared with their singly transgenic littermates. In the bitransgenic mice, the increased steady-state levels of Aβ40 decreased Aβ deposition by 60–90%. These results demonstrate that Aβ42 and Aβ40 have opposing effects on amyloid deposition: Aβ42 promotes amyloid deposition but Aβ40 inhibits it. In addition, increasing Aβ40 levels protected BRI-Aβ40/Tg2576 mice from the premature-death phenotype observed in Tg2576 mice. The protective properties of Aβ40 with respect to amyloid deposition suggest that strategies that preferentially target Aβ40 may actually worsen the disease course and that selective increases in Aβ40 levels may actually reduce the risk for development of AD.
Overview
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TL;DR
Increasing Aβ40 levels in transgenic mouse models reduced parenchymal and vascular amyloid deposition, contrary to the assumption that Aβ40 promotes plaque formation. Aβ40 directly inhibited Aβ42 aggregation in vitro and also reduced premature death in BRI-Aβ40/Tg2576 mice.
Key findings
- In BRI-Aβ40/Tg2576 mice, increased steady-state Aβ40 levels decreased Aβ deposition by 60–90%; RIPA-insoluble, formic acid-extractable Aβ40 and Aβ42 levels were reduced by 60–80% in forebrain and hindbrain, and CAA severity score and affected leptomeningeal vessels decreased by ~60 and ~30% at 15 and 20 months, respectively.
- In BRI-Aβ40/BRI-Aβ42A mice at 8 months, Aβ plaque burden, ThioS-positive cored plaques in cerebellum, and formic acid-extractable Aβ42 were significantly decreased by ~75%, despite soluble brain Aβ (Aβ40 plus Aβ42) being increased ~10-fold compared with BRI-Aβ42A littermates.
- Premature death was modulated by Aβ: BRI-Aβ40/BRI-Aβ42A mice approached 100% death by 16 months, BRI-Aβ42A/Tg2576 mice had ~50% premature death versus ~30% in Tg2576 littermates, while BRI-Aβ40/Tg2576 mice had ~10% death at 7 months.
- In vitro, adding Aβ40 to Aβ42 reduced formation of high-molecular-weight Aβ42 aggregates, leaving most Aβ42 as low-molecular-weight species.
Methods
- Hemizygous BRI-Aβ40 mice were crossed with Tg2576 (APPswe) mice and with BRI-Aβ42A or BRI-Aβ42B mice; littermates were compared across aging series (8–20 months), with n = 5–7 mice per genotype at each age group.
- Parenchymal amyloid burden and ThioS-positive cored plaques were quantified by immunohistochemistry; CAA was scored in leptomeningeal vessels; Aβ levels were measured by sandwich ELISA; APP/C99 levels by Western blot; survival by Kaplan-Meier analysis; and Aβ aggregation by nondenaturing gel assay with synthetic Aβ40/Aβ42 peptides.
- Statistical analyses used ANOVA with Holm-Sidak post hoc tests, t tests, nonparametric tests where needed, and multiple linear regression with no intercept to test additive Aβ levels.
Limitations
- The paper states that extensive premature death in BRI-Aβ40/BRI-Aβ42A mice limited rigorous pathological analyses to an 8-month time point.
- The paper states that it is difficult to completely exclude other transgene-related and genetic background effects, and that premature death rate/extent is influenced by total Aβ levels, Aβ40:Aβ42 ratio, and genetic background.
- The paper states that additional studies are needed to understand factors promoting Aβ40 accumulation within vessels and to investigate effects of increased Aβ40 on oligomer formation and behavioral abnormalities; evident from the text, the work is in mouse models and in vitro assays, with no human AD cohort or cognitive/behavioral therapeutic testing reported.
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34 Own result · 5 No full text of the sources · 4 Own interpretation · 2 Not checked yet · 1 Supported · 1 No basis given
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In the paper
“accumulates to a variable degree in the human AD brain”
- Also stated in: § Introduction · plain
“A40 does accumulate in the AD brain, but the extent of A40 accumulation relative to A42 is highly variable and is usually attributed to accumulation of A40 in cerebral vessels (Gravina et al., 1995).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Abstract
What the sources say
- Supportedcites Gravina et al., 1995 source
The paper’s opening summary reports that 18 of 27 AD brains contained increasing amounts of Aβ ending at Aβ40. It also says that widely varying amounts were deposited in the remaining AD brains, primarily in blood vessel walls. (LLM, conf=0.94)
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- Also stated in: § Introduction · plain
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In the paper
“There was a significant decrease in both the A plaque burden and number of ThioS-positive plaques in BRI-A40/Tg2576 mice compared with Tg2576 littermates ( p Ͻ 0.05).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“Extensive premature death observed in BRI-A40/BRI-A42A mice limited rigorous pathological analyses to an 8 month time point (see Fig.7A).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“There was a significant decrease in both the A plaque burden and number of ThioS-positive plaques in BRI-A40/Tg2576 mice compared with Tg2576 littermates ( p Ͻ 0.05).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“BRI-A42A/Tg2576 mice had a significantly increased premature death rate compared with Tg2576 littermates ( p Ͻ 0.05).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“A, RIPA-insoluble, FA-extractable A40 and A42 levels in the forebrain of BRI-A40/Tg2576 were significantly reduced compared with Tg2576 littermates at all ages (A40 levels at p ϭ 0.01, p Ͻ 0.001, and p Ͻ 0.001 at 11, 15, and 20 months, respectively, and A42 levels at p Ͻ 0.001 at all age).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“There was no difference in survival rates for Tg2576 progeny from breeding with either BRI-A40 mice or BRI-A42A mice ( p ϭ 0.884), thus Tg2576 data were pooled.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“At this age, A plaque burden, the number of ThioS-positive cored plaques in the cerebellum, and FA-fraction A42 levels were significantly decreased by ϳ75% in BRI-A40/BRI-A42A mice (Fig.4), although steady-state soluble brain A (A40 plus A42) levels were increased by ϳ10-fold in bitransgenic mice compared with BRI-A42A littermates (Fig.5D).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“At this age, A plaque burden, the number of ThioS-positive cored plaques in the cerebellum, and FA-fraction A42 levels were significantly decreased by ϳ75% in BRI-A40/BRI-A42A mice (Fig.4), although steady-state soluble brain A (A40 plus A42) levels were increased by ϳ10-fold in bitransgenic mice compared with BRI-A42A littermates (Fig.5D).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“A, RIPA-insoluble, FA-extractable A40 and A42 levels in the forebrain of BRI-A40/Tg2576 were significantly reduced compared with Tg2576 littermates at all ages (A40 levels at p ϭ 0.01, p Ͻ 0.001, and p Ͻ 0.001 at 11, 15, and 20 months, respectively, and A42 levels at p Ͻ 0.001 at all age).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“D, Both the severity of CAA and the number of CAA-affected vessels in cerebellar leptomeninges were reduced in BRI-A40/BRI-A42A mice compared with BRI-A42A mice ( p Ͻ 0.001; rank sum test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“C, Similarly, RIPA-insoluble, FA-extractable A42 levels in the cerebellum of BRI-A40/BRI-A42A mice were markedly lower compared with BRI-A42A littermates ( p ϭ 0.01; t test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“At this age, A plaque burden, the number of ThioS-positive cored plaques in the cerebellum, and FA-fraction A42 levels were significantly decreased by ϳ75% in BRI-A40/BRI-A42A mice (Fig.4), although steady-state soluble brain A (A40 plus A42) levels were increased by ϳ10-fold in bitransgenic mice compared with BRI-A42A littermates (Fig.5D).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“There was an ϳ80% reduction in FA-A42 in the hindbrain of bitransgenic BRI-A40/Tg2576 mice compared with single transgenic Tg2576 littermates ( p ϭ 0.022 by rank sum test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“C99 and APP levels were equivalent between non-Tg and BRI-A40 mice that express only endogenous mouse APP ( p Ͼ 0.1).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“C, D, The relative levels of C99 (C) and APP (D) after normalization to -actin were equivalent between Tg2576 mice and BRI-A40/Tg2576 mice, indicating that there was no alteration in the processing of APP in the bitransgenic mice ( p Ͼ 0.1).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“BRI-A40/ BRI-A42A mice also had markedly less CAA than BRI-A42A littermates (Fig.4 D).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“B, Both the A plaque burden ( p ϭ 0.007; t test) and the number of ThioS-positive plaques ( p Ͻ 0.001; t test) were significantly reduced in BRI-A40/BRI-A42A mice compared with age-matched BRI-A42A littermates.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“C, D, The relative levels of C99 (C) and APP (D) after normalization to -actin were equivalent between Tg2576 mice and BRI-A40/Tg2576 mice, indicating that there was no alteration in the processing of APP in the bitransgenic mice ( p Ͼ 0.1).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“A-C, The levels of RIPA-soluble A40 and A42 in forebrain (A), hindbrain (B), and plasma (C) of BRI-A40/Tg2576 mice were consistent with an additive sumofAlevelsfromtheirsingletransgeniclittermatesat8monthsofage( pϾ0.1).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“D, Both the severity of CAA and the number of CAA-affected vessels in cerebellar leptomeninges were reduced in BRI-A40/BRI-A42A mice compared with BRI-A42A mice ( p Ͻ 0.001; rank sum test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“BRI-A40/BRI-A42B mice had a decreased premature death rate compared with BRI-A40/BRI-A42A mice ( p Ͻ 0.01).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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
“There was no evidence for accumulation of insoluble A in the BRI-A40 mice at any age.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“B, Both the A plaque burden ( p ϭ 0.007; t test) and the number of ThioS-positive plaques ( p Ͻ 0.001; t test) were significantly reduced in BRI-A40/BRI-A42A mice compared with age-matched BRI-A42A littermates.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaindirect- 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
“At this age, A plaque burden, the number of ThioS-positive cored plaques in the cerebellum, and FA-fraction A42 levels were significantly decreased by ϳ75% in BRI-A40/BRI-A42A mice (Fig.4), although steady-state soluble brain A (A40 plus A42) levels were increased by ϳ10-fold in bitransgenic mice compared with BRI-A42A littermates (Fig.5D).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaindirect- 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
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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
“C, D, At both 15 (C) and 20 (D) months of age, there was a decrease in both the CAA severity score and number of CAA-affected vessels in BRI-A40/Tg2576 mice compared with Tg2576 age-matched littermates ( p Ͻ 0.05; t test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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
“C, D, At both 15 (C) and 20 (D) months of age, there was a decrease in both the CAA severity score and number of CAA-affected vessels in BRI-A40/Tg2576 mice compared with Tg2576 age-matched littermates ( p Ͻ 0.05; t test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Numerous studies have established a pivotal role for A42 in Alzheimer's disease (AD) pathogenesis.”
- Also stated in: § Introduction · boosted
“Studies of AD-causing mutations in APP, presenilin 1 (PSEN1), and presenilin 2 (PSEN2) genes demonstrate that the vast majority of these mutations alter APP processing in a manner that either increases the absolute or relative levels of A42 (Price et al., 1998).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Abstract
What the sources say
- Not checked — no full text of the sourcecites Price et al., 1998 source
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
“Indeed, strategies that preferentially target A40 production, as some ␥-secretase inhibitors do, could exacerbate amyloid deposition.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
In the paper
“In vitro, A42 aggregates into amyloid much more rapidly than A40 (Caughey and Lansbury, 2003).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Introduction
What the sources say
- Not checked — no full text of the sourcecites Caughey and Lansbury, 2003 source
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In the paper
“Thus, a common mechanism underlying many neurodegenerative diseases characterized by accumulation of misfolded proteins may be an imbalance between pro-amyloidogenic (i.e., A42 and ␣-synuclein) and antiamyloidogenic (i.e., A40 and -synuclein) proteins.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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In the paper
“The results from BRI-A40/BRI-A42A mice confirmed our findings from BRI-A40/Tg2576 mice, indicating A40 inhibited amyloid deposition in vivo.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
- It may state two separate claims as one. 7
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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
“Bitransgenic BRI-A40/BRI-A42A had an accelerated mortality, whereas non-Tg, single transgenic BRI-A40, and BRI-A42A mice did not show any premature death ( p Ͻ 0.01).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > 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
“Although BRI-A40/Tg2576 only had 10% premature death at 7 months of age, Tg2576 mice had ϳ30% early death ( p Ͻ 0.01).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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.
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
“Decreased FA-A40 levels were also detected but did not reach statistical significance ( p ϭ 0.101 by rank sum test).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
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.
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
“After a 2 h incubation, the A42-only preparation (A40:A42 ratio; 0:1) formed very high molecular weight (HMW) aggregates (indicated by”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > 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
“When A40 was mixed with A42 (A40:A42 ratio; 0.5:1 and 1:1), A40 inhibited the formation of HMW A42 aggregates, and the vast majority of A42 remained as LMW species (indicated by 4 at the bottom of the blot).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > 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: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In vivo, A42 is the predominant form of A that accumulates in the AD brain and is essential for seeding A deposition (Younkin, 1998;Fryer and Holtzman, 2005).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Introduction
What the sources say
- Not checked — no full text of the sourcecites Younkin, 1998 source
- Not matchedcites Fryer and Holtzman, 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
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. It may state two separate claims as one.
In the paper
“-Synuclein inhibits ␣-synuclein aggregation in mice, and mouse tau may retard human tau aggregation (Rochet et al., 2000;Hashimoto et al., 2001;Andorfer et al., 2003).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
What the sources say
- Not checked — no full text of the sourcecites Hashimoto et al., 2001 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.
In the paper
“although A40 is the predominant form of amyloid  (A) produced”
- Also stated in: § Introduction · plain
“Sequential amyloid  precursor protein (APP) processing by -secretase and ␥-secretase produces a major A species, A1-40, and a number of minor species, including A1-42 (Steiner and Haass, 2000).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Abstract
What the sources say
- Not checked — no full text of the sourcecites Steiner and Haass, 2000 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.
- Also stated in: § Introduction · plain
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 inhibition of amyloid deposition by A40 may have critical implications for AD therapy.”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
hedgedconditional- 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.
- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
None of the sources cited for this claim have been checked yet.
In the paper
“BRI-A42A mice initially develop amyloid deposition in the cerebellum at ϳ3 months of age, whereas forebrain pathology was consistently observed only after ϳ12 months of age(McGowan et al., 2005).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
What the sources say
- Not checked yetcites McGowan et al., 2005 source
Checked before — its earlier verdict is held back until a new check runs.
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.
- Not checked yet
In the paper
“-Synuclein inhibits ␣-synuclein aggregation in mice, and mouse tau may retard human tau aggregation (Rochet et al., 2000;Hashimoto et al., 2001;Andorfer et al., 2003).”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Discussion
What the sources say
- Not checked — no full text of the sourcecites Andorfer et al., 2003 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.
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
“its role in AD pathogenesis has not been established”
§ Neurobiology of Disease A40 Inhibits Amyloid Deposition In Vivo > Abstract
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.
The paper relies on this without support.
Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
“The inhibition of amyloid deposition by A40 may have critical implications for AD therapy.”
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
“By crossing BRI2-A1-40 or BRI-A1-42 transgenic mice with Tg2576 mice, we previously demonstrated that A1-40 and A42 have opposing effects on amyloid deposition (McGowan et al., 2005;Kim et al., 2007).”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Kim et al., 2007
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
“Aβ40 is present in larger amounts in the brain, yet Aβ42 is more neurotoxic and has a higher tendency to aggregate.8–11”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [9]
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
“Almost all previous studies investigating the effect of bifunctional compounds on the neurotoxicity of metal-Aβ species have focused on the less neurotoxic and possibly even anti-amyloidogenic Aβ40 peptide.9,97,98”
From Bifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ42Peptide (2012) · cites this paper as [9]
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
“Aβ species, including the most abundant Aβ40 and more toxic Aβ42, are produced by two sequential proteolytic cleavages of amyloid precursor protein (APP) by β- and γ-secretases (Kim et al., 2007; McGowan et al., 2005).”
From Apolipoprotein E in Synaptic Plasticity and Alzheimer’s Disease: Potential Cellular and Molecular Mechanisms (2014) · cites this paper as Kim et al., 2007
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Several methods were used, including a native gel assay previously used to demonstrate that A1-40 inhibits A1-42 aggregation (Kim et al., 2007).”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Kim et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“The reduction in A deposition observed in the mice expressing the rAAV1 BRI2-A1-40 transgene was consistent with our previous transgenic mice studies (Kim et al., 2007), whereas the reduction of A deposition observed in the mice expressing BRI2 was unexpected.”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Kim et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“The studies with BRI2-A1-40 confirmed previous studies obtained using conventional transgenic mice expressing BRI2-A1-40 (McGowan et al., 2005;Kim et al., 2007).”
From BRI2 (ITM2b) Inhibits A Deposition In Vivo (2008) · cites this paper as Kim et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“Such high concentrations may artificially cause Aβ40 to aggregate without an Aβ42 seeding nucleus, despite the fact that Aβ40 has an anti-amyloidogenic effect in vivo (Kim et al., 2007).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Kim et al., 2007
The cited source says what the claim attributes to it.
In the citing paper
“Several recent studies suggest that Aβ40 and Aβ42 may have opposing effects on Aβ aggregation in vivo (Kim et al., 2007; McGowan et al., 2005).”
From The role of apolipoprotein E in Alzheimer's disease (2009) · cites this paper as Kim et al., 2007
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Self-check results appear here once an independent check has confirmed them.
Cited works that were retracted
Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.
A note, not an issue: for example, a cited work that was retracted only after this paper was published, which its authors could not have known.
In the paper
“…2003; Lombardo et al., 2003; Tsai et al., 2004), an increasing body of evidence suggests that soluble oligomeric and protofibrillar A species, such as A *56, may cause the synaptic dysfunction and memory deficits in mice (Klein et al., 2004; Cleary et al., 2005; Glabe, 2006; Lesne et al., 2006).”
Cited work 10.1038/nature04533 · retracted 2024-06-24 · notice 10.1038/s41586-024-07691-8 · this paper published 2007-01-17
Citations
Cites
1 retracted
RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory
Lesné, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., & Ashe, K. H. (2006) · Nature · doi:10.1038/nature04533 · Cited by 2,769 · cited 1×
“…2003; Lombardo et al., 2003; Tsai et al., 2004), an increasing body of evidence suggests that soluble oligomeric and protofibrillar A species, such as A *56, may cause the synaptic dysfunction and memory deficits in mice (Klein et al., 2004; Cleary et al., 2005; Glabe, 2006; Lesne et al., 2006).”
BackgroundRetractedThe Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210 · cited 3×
“…BRI-A 40/Tg2576 mice We crossed hemizygous BRI-A 40 mice that produce only A 40 with hemizygous APPswe (Tg2576) mice overexpressing a normal profile of human A peptides (Hsiao et al., 1996), generating offspring with nontransgenic (non-Tg), BRI-A 40, Tg2576, and BRI-A 40/Tg2576 genotypes.”
BackgroundMethodInfluentialMucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856 · cited 1×
“Finally, results from transgenic mice expressing wild-type and various mutant forms of APP also suggest that increased A 40 levels might reduce amyloid deposition (Mucke et al., 2000).”
BackgroundNatural oligomers of the amyloid-β protein specifically disrupt cognitive function
Cleary, J. P., Walsh, D. M., Hofmeister, J. J., Shankar, G. M., Kuskowski, M. A., Selkoe, D. J., & Ashe, K. H. (2004) · Nature Neuroscience · doi:10.1038/nn1372 · Cited by 1,722 · cited 2×
“, 2004), an increasing body of evidence suggests that soluble oligomeric and protofibrillar A species, such as A *56, may cause the synaptic dysfunction and memory deficits in mice (Klein et al., 2004; Cleary et al., 2005; Glabe, 2006; Lesne et al., 2006).”
BackgroundCaughey, B., & Lansbury, P. T. (2003) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.26.010302.081142 · Cited by 1,650 · cited 3×
“In vitro, A 42 aggregates into amyloid much more rapidly than A 40 (Caughey and Lansbury, 2003).”
BackgroundA subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity
Weggen, S., Eriksen, J. L., Das, P., Sagi, S. A., Wang, R., Pietrzik, C. U., Findlay, K. A., Smith, T. E., Murphy, M. P., Bulter, T., et al. (2001) · Nature · doi:10.1038/35102591 · Cited by 1,388 · cited 1×
“Our data support the strategy that selectively targeting A 42 by allosterically modulating -secretase may be preferential to nonselective inhibition of -secretase activity (Weggen et al., 2001; Eriksen et al., 2003; Lleo et al., 2004).”
MethodSelf-citationKawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-02-00372.2001 · Cited by 1,053 · cited 2×
“3 (anti-A 35-42 Ab) as the capture Ab for A 42, and Ab9 –HRP as the detection Ab for A 42, as described previously (Kawarabayashi et al., 2001) (n 5–7 mice per genotype at each age group).”
MethodInfluentialLeissring, M. A., Farris, W., Chang, A. Y., Walsh, D. M., Wu, X., Sun, X., Frosch, M. P., & Selkoe, D. J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00787-6 · Cited by 725
Cited by
Sorted by citations
The amyloid hypothesis of Alzheimer's disease at 25 years
Selkoe, D. J., & Hardy, J. (2016) · EMBO Molecular Medicine · doi:10.15252/emmm.201606210 · Cited by 6,164
“Ab42, Ab43, and longer Ab peptides are highly self-aggregating, whereas Ab40 may actually be antiamyloidogenic (Kim et al, 2007).”
BackgroundKarran, E., Mercken, M., & Strooper, B. D. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3505 · Cited by 2,188
The role of apolipoprotein E in Alzheimer's disease
Kim, J., Basak, J. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.06.026 · Cited by 1,661
Self-citationAlzheimer’s Disease: The Challenge of the Second Century
Holtzman, D. M., Morris, J. C., & Goate, A. M. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002369 · Cited by 1,424
Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
Kametani, F., & Hasegawa, M. (2018) · Frontiers in Neuroscience · doi:10.3389/fnins.2018.00025 · Cited by 836
“…and Aβ amyloid fibrils were present in Aβ42-overexpressing BRI2-Aβ mice, and amyloid deposits and formation of senile plaques were observed in the brain, degeneration of nerve cells and neuronal loss were not observed, and there was no impairment of cognitive functions (Kim et al., 2007, 2013).”
Background
Metadata
- Authors
- Kim, J., Onstead, L., Randle, S., Price, R., Smithson, L., Zwizinski, C., Dickson, D. W., Golde, T., & McGowan, E.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2007-01-17
- Volume
- 27
- Issue
- 3
- Pages
- 627-633
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6672801
- OpenAlex
- W2016811754
- Semantic Scholar
- cdc788c9481c38fa796d91320b21decd840d7619
- Cited by
- 359
- References
- 52
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 17 · 2023: 20 · 2022: 16 · 2021: 19 · 2020: 14 · 2019: 21 · 2018: 11 · 2017: 14 · 2016: 21 · 2015: 16 · 2014: 21 · 2013: 27 · 2012: 16
- FWCI
- 17.59
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- Mayo Foundation for Medical Education and Research
- National Institute on Aging (R01AG022595)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Aβ40, amyloid-beta 42, Alzheimer's disease, amyloid deposition, amyloid plaques, Tg2576 mice, bitransgenic mice, cerebrovascular amyloid
- MeSH terms
- Amyloid, Animals, Humans, Mice, Inbred C57BL, Mice, Transgenic, Peptide Fragments, Amyloid beta-Peptides, Mice, Plaque, Amyloid
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 2026-10-17, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-17 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (gpt-6-sol).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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