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.
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Written from the paper’s full text.
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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Claims the paper makes
1 of 9 cited sources checked · 1 supported · 0 flagged
- Premisecitation
Aβ40 accumulates to a variable degree in the human AD brain.
“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).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Gravina et al., 1995 source
- Also stated in: § Introduction · plain
- Findingown data
The number of ThioS-positive cored plaques was significantly decreased in BRI-Aβ40/Tg2576 mice compared with Tg2576 littermates at 15 and 20 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
Extensive premature death observed in BRI-Aβ40/BRI-Aβ42A mice limited rigorous pathological analyses to an 8 month time point.
“Extensive premature death observed in BRI-A40/BRI-A42A mice limited rigorous pathological analyses to an 8 month time point (see Fig.7A).”
Quote in the paperNot a substantial claim - Findingown data
Aβ plaque burden was significantly decreased in BRI-Aβ40/Tg2576 mice compared with Tg2576 littermates at 15 and 20 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
BRI-Aβ42A/Tg2576 mice had a significantly increased premature death rate compared with Tg2576 littermates.
“BRI-A42A/Tg2576 mice had a significantly increased premature death rate compared with Tg2576 littermates ( p Ͻ 0.05).”
Quote in the paperSubstantial claim
- Findingown data
RIPA-insoluble, FA-extractable Aβ40 levels in the forebrain of BRI-Aβ40/Tg2576 mice were significantly reduced compared with Tg2576 littermates at 11, 15, and 20 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
There was no difference in survival rates for Tg2576 progeny from breeding with either BRI-Aβ40 mice or BRI-Aβ42A mice.
“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.”
Quote in the paperSubstantial claim - Findingown data
At 8 months of age, Aβ plaque burden in the cerebellum was significantly decreased by ~75% in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
Steady-state soluble brain Aβ (Aβ40 plus Aβ42) levels were increased by ~10-fold in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
RIPA-insoluble, FA-extractable Aβ42 levels in the forebrain of BRI-Aβ40/Tg2576 mice were significantly reduced compared with Tg2576 littermates at all ages.
“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).”
Quote in the paperSubstantial claim - Findingown data
The number of CAA-affected vessels in cerebellar leptomeninges was reduced in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A mice.
“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).”
Quote in the paperSubstantial claim - Findingown data
RIPA-insoluble, FA-extractable Aβ42 levels in the cerebellum of BRI-Aβ40/BRI-Aβ42A mice were markedly lower compared with BRI-Aβ42A littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
At 8 months of age, FA-fraction Aβ42 levels were significantly decreased by ~75% in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
There was an ~80% reduction in FA-Aβ42 in the hindbrain of bitransgenic BRI-Aβ40/Tg2576 mice compared with single transgenic Tg2576 littermates at 20 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
C99 and APP levels were equivalent between non-Tg and BRI-Aβ40 mice that express only endogenous mouse APP.
“C99 and APP levels were equivalent between non-Tg and BRI-A40 mice that express only endogenous mouse APP ( p Ͼ 0.1).”
Quote in the paperSubstantial claim - Findingown data
There was no accumulation of RIPA-insoluble FA-Aβ in BRI-Aβ40 mice.
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
Quote in the paperSubstantial claim - Findingown data
The relative levels of C99 after normalization to β-actin were equivalent between Tg2576 mice and BRI-Aβ40/Tg2576 mice, indicating no alteration in APP processing in the bitransgenic mice.
“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).”
Quote in the paperSubstantial claim - Findingown data
BRI-Aβ40/BRI-Aβ42A mice had markedly less CAA than BRI-Aβ42A littermates.
“BRI-A40/ BRI-A42A mice also had markedly less CAA than BRI-A42A littermates (Fig.4 D).”
Quote in the paperSubstantial claim - Findingown data
The number of ThioS-positive plaques was significantly reduced in BRI-Aβ40/BRI-Aβ42A mice compared with age-matched BRI-Aβ42A littermates at 8 months of age.
“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.”
Quote in the paperSubstantial claim - Findingown data
The relative levels of APP after normalization to β-actin were equivalent between Tg2576 mice and BRI-Aβ40/Tg2576 mice, indicating no alteration in APP processing in the bitransgenic mice.
“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).”
Quote in the paperSubstantial claim - Findingown data
The levels of RIPA-soluble Aβ40 and Aβ42 in forebrain, hindbrain, and plasma of BRI-Aβ40/Tg2576 mice were consistent with an additive sum of Aβ levels from their single transgenic littermates at 8 months of age.
“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).”
Quote in the paperSubstantial claim - Findingown data
The severity of CAA in cerebellar leptomeninges was reduced in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A mice.
“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).”
Quote in the paperSubstantial claim - Findingown data
BRI-Aβ40/BRI-Aβ42B mice had a decreased premature death rate compared with BRI-Aβ40/BRI-Aβ42A mice.
“BRI-A40/BRI-A42B mice had a decreased premature death rate compared with BRI-A40/BRI-A42A mice ( p Ͻ 0.01).”
Quote in the paperSubstantial claim - Findingown data
There was no CAA in BRI-Aβ40 mice.
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
Quote in the paperSubstantial claim - Findingown data
There was no evidence for accumulation of insoluble Aβ in the BRI-Aβ40 mice at any age.
“There was no evidence for accumulation of insoluble A in the BRI-A40 mice at any age.”
Quote in the paperSubstantial claim - Findingown data
Aβ plaque burden was significantly reduced in BRI-Aβ40/BRI-Aβ42A mice compared with age-matched BRI-Aβ42A littermates at 8 months of age.
“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.”
Quote in the paperSubstantial claim - Findingown data
At 8 months of age, the number of ThioS-positive cored plaques in the cerebellum was significantly decreased by ~75% in BRI-Aβ40/BRI-Aβ42A mice compared with BRI-Aβ42A littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
There was no amyloid pathology in BRI-Aβ40 mice.
“There was no amyloid pathology, CAA, or accumulation of RIPA-insoluble FA-A in BRI-A40 mice.”
Quote in the paperSubstantial claim - Findingown data
At 15 and 20 months of age, there was a decrease in number of CAA-affected vessels in BRI-Aβ40/Tg2576 mice compared with Tg2576 age-matched littermates.
“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).”
Quote in the paperSubstantial claim - Findingown data
At 15 and 20 months of age, there was a decrease in CAA severity score in BRI-Aβ40/Tg2576 mice compared with Tg2576 age-matched littermates.
“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).”
Quote in the paperSubstantial claim - Premisecitation
Aβ42 plays a pivotal role in Alzheimer's disease pathogenesis.
“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).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Price et al., 1998 source
- Also stated in: § Introduction · boosted
- Interpretationreasoning
Strategies that preferentially target Aβ40 production, as some γ-secretase inhibitors do, could exacerbate amyloid deposition.
“Indeed, strategies that preferentially target A40 production, as some ␥-secretase inhibitors do, could exacerbate amyloid deposition.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
- Premisecitation
In vitro, Aβ42 aggregates into amyloid much more rapidly than Aβ40.
“In vitro, A42 aggregates into amyloid much more rapidly than A40 (Caughey and Lansbury, 2003).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Caughey and Lansbury, 2003 source
- Interpretationreasoning
A common mechanism underlying many neurodegenerative diseases characterized by accumulation of misfolded proteins may be an imbalance between pro-amyloidogenic (i.e., Aβ42 and α-synuclein) and antiamyloidogenic (i.e., Aβ40 and β-synuclein) proteins.
“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.”
Quote in the paperSubstantial claim - Interpretationown data
Aβ40 inhibited amyloid deposition in vivo.
“The results from BRI-A40/BRI-A42A mice confirmed our findings from BRI-A40/Tg2576 mice, indicating A40 inhibited amyloid deposition in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
- May combine two claims. 7
- Classified as probably not a substantial claim. 6
May combine two claims.
Findingown dataBitransgenic BRI-Aβ40/BRI-Aβ42A mice had an accelerated mortality, whereas non-Tg, single transgenic BRI-Aβ40, and BRI-Aβ42A mice did not show any premature death.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBRI-Aβ40/Tg2576 mice had only 10% premature death at 7 months of age, whereas Tg2576 mice had ~30% early death.
“Although BRI-A40/Tg2576 only had 10% premature death at 7 months of age, Tg2576 mice had ϳ30% early death ( p Ͻ 0.01).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataDecreased FA-Aβ40 levels were detected in BRI-Aβ40/Tg2576 mice compared with Tg2576 littermates but did not reach statistical significance.
“Decreased FA-A40 levels were also detected but did not reach statistical significance ( p ϭ 0.101 by rank sum test).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAfter a 2 h incubation, the Aβ42-only preparation formed very high molecular weight (HMW) aggregates without any low molecular weight (LMW) species, whereas the Aβ40-only preparation remained as a LMW species.
“After a 2 h incubation, the A42-only preparation (A40:A42 ratio; 0:1) formed very high molecular weight (HMW) aggregates (indicated by”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataWhen Aβ40 was mixed with Aβ42 at ratios 0.5:1 and 1:1, Aβ40 inhibited the formation of HMW Aβ42 aggregates, and the vast majority of Aβ42 remained as LMW species.
“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).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationIn vivo, Aβ42 is the predominant form of Aβ that accumulates in the AD brain and is essential for seeding Aβ deposition.
“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).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Younkin, 1998 source
- cites Fryer and Holtzman, 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationβ-Synuclein inhibits α-synuclein aggregation in mice.
“-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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hashimoto et al., 2001 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAβ40 is the predominant form of amyloid β produced.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Steiner and Haass, 2000 source
- Also stated in: § Introduction · plain
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationown dataThe inhibition of amyloid deposition by Aβ40 may have critical implications for AD therapy.
“The inhibition of amyloid deposition by A40 may have critical implications for AD therapy.”
Quote in the paperNot a substantial claim- Rests on an assumption: Findings in transgenic mouse models of amyloid deposition are relevant to human Alzheimer's disease therapy.
May combine two claims.
PremisecitationBRI-Aβ42A mice initially develop amyloid deposition in the cerebellum at ~3 months of age, whereas forebrain pathology is consistently observed only after ~12 months of age.
“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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McGowan et al., 2005 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationMouse tau may retard human tau aggregation.
“-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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Andorfer et al., 2003 source
Classified as probably not a substantial claim.
Premisenone givenThe role of Aβ40 in AD pathogenesis has not been established.
“its role in AD pathogenesis has not been established”
Quote in the paperSubstantial 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?
Aβ1-40 and Aβ42 have opposing effects on amyloid deposition in BRI2-Aβ transgenic mice crossed with Tg2576 mice.
“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
The Results section reports 60–90% less amyloid deposition in BRI-Aβ40/Tg2576 mice than in Tg2576 littermates. The Abstract states that Aβ42 promotes deposition while Aβ40 inhibits it, and the Generation of mice section says both BRI lines were crossed with Tg2576. But the passages do not establish the opposing effects on deposition by comparing both types of Tg2576 cross; the Aβ42 deposition evidence described in the Introduction concerns BRI-Aβ42 mice. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAβ40 is present in larger amounts in the brain, yet Aβ42 is more neurotoxic and has a higher tendency to aggregate.
“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 Aβ<sub>42</sub>Peptide (2012) · cites this paper as [9]
The Introduction says Aβ40 is the predominant form produced, but it also says Aβ42 is the predominant form that accumulates in the AD brain; thus, the claim about larger amounts in the brain needs qualification. The Introduction and aggregation-assay section support Aβ42’s greater tendency to aggregate. The copy does not establish that Aβ42 is more neurotoxic than Aβ40. Passage-level page numbers were not provided. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAlmost 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.
“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 Aβ<sub>42</sub>Peptide (2012) · cites this paper as [9]
The Discussion (pp. 627–633; exact page not identified in our copy) describes Aβ40 as antiamyloidogenic, and the Introduction reports reduced amyloid deposition when Aβ40 levels increased in mice. Our copy does not establish that almost all prior studies of bifunctional compounds focused on Aβ40, or that Aβ40 is less neurotoxic in metal–Aβ species. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAβ 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.
“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
The Introduction (page not provided) states that sequential β- and γ-secretase processing of APP produces Aβ1-40 as a major species and Aβ1-42 as a minor species. It also reports that Aβ42 aggregates more rapidly and has a greater role in amyloid deposition, but it does not establish the claim that Aβ42 is more toxic. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAβ1-40 inhibits Aβ1-42 aggregation.
“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 reduction in Aβ deposition in mice expressing the rAAV1 BRI2-Aβ1-40 transgene was consistent with previous transgenic mice studies.
“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 somatic brain transgenic BRI2-A1-40 studies confirmed previous studies using conventional transgenic mice expressing BRI2-A1-40.
“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
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.
“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
Several recent studies suggest that Aβ40 and Aβ42 may have opposing effects on Aβ aggregation in vivo.
“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
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Cites a retracted work: 10.1038/nature04533
InfoThe cited work was retracted on 2024-06-24 (notice 10.1038/s41586-024-07691-8), not before this paper was published (2007-01-17).
Cited work 10.1038/nature04533 · retracted 2024-06-24 · notice 10.1038/s41586-024-07691-8 · this paper published 2007-01-17
“…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).”
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× · see citing works
“…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 · see citing works
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 · see citing works
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× · see citing works
“…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× · see citing works
“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 1,677 · cited 2× · see citing works
“, 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× · see citing works
“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× · see citing works
“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× · see citing works
“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).”
MethodInfluentialHyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms
Andorfer, C., Kress, Y., Espinoza, M., De Silva, R., Tucker, K. L., Barde, Y., Duff, K., & Davies, P. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01879.x · Cited by 722 · cited 1× · see citing works
“-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).”
BackgroundLeissring, 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 708 · see citing works
Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain
Gravina, S. A., Ho, L., Eckman, C. B., Long, K. E., Otvos, L., Younkin, L. H., Suzuki, N., & Younkin, S. G. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.13.7013 · Cited by 676 · cited 2× · see citing works
“This is a surprising result given that A 40 is reported to be the predominant A species deposited in vessels (Gravina et al., 1995).”
BackgroundMoechars, D., Dewachter, I., Lorent, K., Reversé, D., Baekelandt, V., Naidu, A., Tesseur, I., Spittaels, K., Haute, C. V. D., Checler, F., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.10.6483 · Cited by 668 · cited 3× · see citing works
“In contrast to many lines of mutant APP mice that exhibit a premature-death phenotype (Moechars et al., 1999b; Leissring et al., 2003), BRI-A 40 or BRI-A 42 mice did not have accelerated mortality (Fig.”
BackgroundResultNSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., Weggen, S., Das, P., McLendon, D. C., Ozols, V. V., Jessing, K. W., Zavitz, K. H., Koo, E. H., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci18162 · Cited by 634 · cited 1× · see citing works
“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).”
MethodCommon mechanisms of amyloid oligomer pathogenesis in degenerative disease
Glabe, C. G. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.04.017 · Cited by 569 · cited 2× · see citing works
“, 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).”
BackgroundAβ42 Is Essential for Parenchymal and Vascular Amyloid Deposition in Mice
McGowan, E., Pickford, F., Kim, J., Onstead, L., Eriksen, J., Yu, C., Skipper, L., Murphy, M. P., Beard, J., Das, P., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.06.030 · Cited by 565 · cited 16× · see citing works
“BRI-A 42A mice led to a reduction in CAA, demonstrating that A 40 has anti-amyloidogenic effects on not only parenchymal but also vascular amyloid deposition.”
BackgroundMethodInfluentialSelf-citationFibrillar amyloid deposition leads to local synaptic abnormalities and breakage of neuronal branches
Tsai, J., Grutzendler, J., Duff, K., & Gan, W.-B. (2004) · Nature Neuroscience · doi:10.1038/nn1335 · Cited by 561 · cited 2× · see citing works
“…debate regarding the role of amyloid in AD pathogenesis (Le et al., 2001; Caughey and Lansbury, 2003; D’Amore et al., 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…”
BackgroundHsiao, K., Borchelt, D., Olson, K., Johannsdottir, R., Kitt, C. A., Yunis, W. S., Xu, S., Eckman, C., Younkin, S. G., Price, D., et al. (1995) · Neuron · doi:10.1016/0896-6273(95)90107-8 · Cited by 519 · cited 1× · see citing works
“Premature death has been observed in many mutant APP transgenic mice on multiple background strains, although no one has been able to determine the cause of death (Hsiao et al., 1995; Moechars et al., 1999b; Leissring et al., 2003).”
BackgroundKlein, W. L., Stine, W. B., & Teplow, D. B. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.02.010 · Cited by 487 · cited 2× · see citing works
“, 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).”
BackgroundPresenilin clinical mutations can affect γ‐secretase activity by different mechanisms
Bentahir, M., Nyabi, O., Verhamme, J., Tolia, A., Horré, K., Wiltfang, J., Esselmann, H., & Strooper, B. D. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03578.x · Cited by 412 · cited 1× · see citing works
“Decreases in A 40, without an increase in A 42, have been associated with a subset of AD causing PSEN mutations and the APPV715M mutation (Ancolio et al., 1999; Bentahir et al., 2006; Kumar-Singh et al., 2006).”
BackgroundALZHEIMER'S DISEASE: Genetic Studies and Transgenic Models
Price, D. L., Tanzi, R. E., Borchelt, D. R., & Sisodia, S. S. (1998) · Annual Review of Genetics · doi:10.1146/annurev.genet.32.1.461 · Cited by 406 · cited 1× · see citing works
“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 A 42 (Price et al., 1998).”
Backgroundβ-Synuclein Inhibits α-Synuclein Aggregation
Hashimoto, M., Rockenstein, E., Mante, M., Mallory, M., & Masliah, E. (2001) · Neuron · doi:10.1016/s0896-6273(01)00462-7 · Cited by 398 · cited 1× · see citing works
“-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).”
BackgroundHerzig, M. C., Winkler, D. T., Burgermeister, P., Pfeifer, M., Kohler, E., Schmidt, S. D., Danner, S., Abramowski, D., Stürchler-Pierrat, C., Bürki, K., et al. (2004) · Nature Neuroscience · doi:10.1038/nn1302 · Cited by 391 · cited 1× · see citing works
“Although previous studies suggested that a higher ratio of A 40 to A 42 might promote the formation of CAA over parenchymal deposition (Herzig et al., 2004; Fryer and Holtzman, 2005; Fryer et al., 2005), in other studies, selective increases in A 42 were associated with more CAA (Van Dorpe et al.,…”
ResultSnyder, S. W., Ladror, U. S., Wade, W. S., Wang, G. T., Barrett, L. W., Matayoshi, E. D., Huffaker, H. J., Krafft, G. A., & Holzman, T. F. (1994) · Biophysical Journal · doi:10.1016/s0006-3495(94)80591-0 · Cited by 381 · cited 2× · see citing works
“There are several in vitro studies demonstrating that A 40 directly interferes with A 42 aggregation by delaying the A 42- mediated nucleation step at an early stage in the fibrillogenesis process (Snyder et al., 1994; Hasegawa et al., 1999; Zou et al., 2003).”
BackgroundTherapeutic effects of PKC activators in Alzheimer's disease transgenic mice
Etcheberrigaray, R., Tan, M., Dewachter, I., Kuipéri, C., der Auwera, I. V., Wera, S., Qiao, L., Bank, B., Nelson, T. J., Kozikowski, A. P., et al. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0403921101 · Cited by 343 · cited 1× · see citing works
“Reduction in A levels by increased -secretase activity or by enhanced proteolysis of A has been linked to prevention of high mortality in APP transgenic mice and Drosophila (Leissring et al., 2003; Etcheberrigaray et al., 2004; Finelli et al., 2004).”
BackgroundKumar‐Singh, S., Theuns, J., Broeck, B. V., Pirici, D. N., Vennekens, K., Corsmit, E., Cruts, M., Dermaut, B., Wang, R., & Broeckhoven, C. V. (2006) · Human Mutation · doi:10.1002/humu.20336 · Cited by 320 · cited 1× · see citing works
“Decreases in A 40, without an increase in A 42, have been associated with a subset of AD causing PSEN mutations and the APPV715M mutation (Ancolio et al., 1999; Bentahir et al., 2006; Kumar-Singh et al., 2006).”
BackgroundDiagnosis of Cerebral Amyloid Angiopathy: Sensitivity and Specificity of Cortical Biopsy
Greenberg, S. M., & Vonsattel, J.-P. G. (1997) · Stroke · doi:10.1161/01.str.28.7.1418 · Cited by 312 · cited 1× · see citing works
“Positively stained blood vessels were visually assessed using modified Vonsattel’s scoring system as described previously (Greenberg and Vonsattel, 1997).”
MethodA model for studying Alzheimer's Aβ42-induced toxicity in Drosophila melanogaster
Finelli, A. L., Kelkar, A., Song, H., Yang, H., & Konsolaki, M. (2004) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2004.03.001 · Cited by 286 · cited 1× · see citing works
“Reduction in A levels by increased -secretase activity or by enhanced proteolysis of A has been linked to prevention of high mortality in APP transgenic mice and Drosophila (Leissring et al., 2003; Etcheberrigaray et al., 2004; Finelli et al., 2004).”
BackgroundThe role of Aβ42 in Alzheimer's disease
Younkin, S. G. (1998) · Journal of Physiology-Paris · doi:10.1016/s0928-4257(98)80035-1 · Cited by 282 · cited 1× · see citing works
“In vivo, A 42 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).”
BackgroundFryer, J. D., Simmons, K., Parsadanian, M., Bales, K. R., Paul, S. M., Sullivan, P. M., & Holtzman, D. M. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5170-04.2005 · Cited by 278 · cited 2× · see citing works
“In vivo, A 42 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).”
BackgroundResultLashuel, H. A., Hartley, D. M., Petre, B. M., Wall, J. S., Simon, M. N., Walz, T., & Lansbury, P. T. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00927-6 · Cited by 237 · cited 1× · see citing works
“Additional studies have shown that wild-type A 40 can stabilize aggregation of Arctic mutant A 40 (E22G) (Lashuel et al., 2003).”
BackgroundDorpe, J. V., Smeijers, L., Dewachter, I., Nuyens, D., Spittaels, K., den Haute, C. V., Mercken, M. H., Moechars, D., Laenen, I., Kuipéri, C., et al. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64644-5 · Cited by 223 · cited 1× · see citing works
“…of A 40 to A 42 might promote the formation of CAA over parenchymal deposition (Herzig et al., 2004; Fryer and Holtzman, 2005; Fryer et al., 2005), in other studies, selective increases in A 42 were associated with more CAA (Van Dorpe et al., 2000; Samura et al., 2006; Van Dooren et al., 2006).”
ResultRochet, J., Conway, K. A., & Lansbury, P. T. (2000) · Biochemistry · doi:10.1021/bi001315u · Cited by 221 · see citing works
Interaction between Aβ(1−42) and Aβ(1−40) in Alzheimer's β-Amyloid Fibril Formation in Vitro
Hasegawa, K., Yamaguchi, I., Omata, S., Gejyo, F., & Naiki, H. (1999) · Biochemistry · doi:10.1021/bi991161m · Cited by 217 · cited 1× · see citing works
“There are several in vitro studies demonstrating that A 40 directly interferes with A 42 aggregation by delaying the A 42- mediated nucleation step at an early stage in the fibrillogenesis process (Snyder et al., 1994; Hasegawa et al., 1999; Zou et al., 2003).”
BackgroundNonsteroidal anti-inflammatory drugs lower Aβ42 and change presenilin 1 conformation
Lleó, A., Berezovska, O., Herl, L. D., Raju, S., Deng, A., Bacskai, B. J., Frosch, M. P., Irizarry, M. C., & Hyman, B. T. (2004) · Nature Medicine · doi:10.1038/nm1112 · Cited by 198 · see citing works
Ancolio, K., Dumanchin‐Njock, C., Barelli, H., Warter, J., Brice, A., Campion, D., Frébourg, T., & Checler, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.4119 · Cited by 179 · cited 1× · see citing works
“Decreases in A 40, without an increase in A 42, have been associated with a subset of AD causing PSEN mutations and the APPV715M mutation (Ancolio et al., 1999; Bentahir et al., 2006; Kumar-Singh et al., 2006).”
BackgroundIntramembrane proteolysis by presenilins
Steiner, H., & Haass, C. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35043065 · Cited by 161 · cited 1× · see citing works
“Sequential amyloid precursor protein (APP) processing by -secretase and -secretase produces a major A species, A 1-40, and a number of minor species, including A 1-42 (Steiner and Haass, 2000).”
BackgroundZou, K., Kim, D. S., Kakio, A., Byun, K., Gong, J., Kim, J. W., Kim, M. J., Sawamura, N., Nishimoto, S., Matsuzaki, K., et al. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.02018.x · Cited by 154 · cited 1× · see citing works
“There are several in vitro studies demonstrating that A 40 directly interferes with A 42 aggregation by delaying the A 42- mediated nucleation step at an early stage in the fibrillogenesis process (Snyder et al., 1994; Hasegawa et al., 1999; Zou et al., 2003).”
BackgroundSelf-citationPotential role of presenilin-regulated signaling pathways in sporadic neurodegeneration
Koo, E. H., & Kopan, R. (2004) · Nature Medicine · doi:10.1038/nm1065 · Cited by 154 · cited 1× · see citing works
“In addition, mutations in PSEN can have a variety of effects on protein trafficking, clearance, and intracellular signaling (Koo and Kopan, 2004; Zhang et al., 2006).”
BackgroundAmyloid-β Antibody Treatment Leads to Rapid Normalization of Plaque-Induced Neuritic Alterations
Lombardo, J. A., Stern, E. A., McLellan, M. E., Kajdasz, S. T., Hickey, G. A., Bacskai, B. J., & Hyman, B. T. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-34-10879.2003 · Cited by 149 · cited 2× · see citing works
“Although there is much debate regarding the role of amyloid in AD pathogenesis (Le et al., 2001; Caughey and Lansbury, 2003; D’Amore et al., 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 synapt…”
BackgroundMatsuda, S., Giliberto, L., Matsuda, Y., Davies, P., McGowan, E., Pickford, F., Ghiso, J., Frangione, B., & D'Adamio, L. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500217200 · Cited by 141 · cited 1× · see citing works
“M, Months. creased A and increased C99 levels, with inconclusive effects of BRI on full-length APP and total secreted APP levels (Fotinopoulou et al., 2005; Matsuda et al., 2005).”
BackgroundSelf-citationNSAIDs and enantiomers of flurbiprofen target γ-secretase and lower Aβ42 in vivo
Eriksen, J. L., Sagi, S. A., Smith, T. E., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci200318162 · Cited by 135 · see citing works
BRI2 Interacts with Amyloid Precursor Protein (APP) and Regulates Amyloid β (Aβ) Production
Fotinopoulou, A., Tsachaki, M., Vlavaki, M., Poulopoulos, A., Rostagno, A., Frangione, B., Ghiso, J., & Efthimiopoulos, S. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.c500231200 · Cited by 114 · cited 1× · see citing works
“M, Months. creased A and increased C99 levels, with inconclusive effects of BRI on full-length APP and total secreted APP levels (Fotinopoulou et al., 2005; Matsuda et al., 2005).”
BackgroundKlug, G. M., Lošić, D., Supundi, Subasinghe, S., Aguilar, M., Martin, L. L., & Small, D. H. (2003) · European Journal of Biochemistry · doi:10.1046/j.1432-1033.2003.03815.x · Cited by 107 · cited 2× · see citing works
“Mixtures were run on 4 –20% Tris-HCl gels under nondenaturing conditions and transferred to a 0.4 m polyvinylidene difluoride membrane as described previously (Klug et al., 2003).”
MethodInfluentialLe, R., Cruz, L., Urbanc, B., Knowles, R. B., Ashe, K. H., Duff, K., Irizarry, M. C., Stanley, E., & Hyman, B. T. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.8.753 · Cited by 90 · cited 2× · see citing works
“Although there is much debate regarding the role of amyloid in AD pathogenesis (Le et al., 2001; Caughey and Lansbury, 2003; D’Amore et al., 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 synapt…”
BackgroundD'Amore, J. D., Kajdasz, S. T., McLellan, M. E., Bacskai, B. J., Stern, E. A., & Hyman, B. T. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.2.137 · Cited by 89 · cited 2× · see citing works
“Although there is much debate regarding the role of amyloid in AD pathogenesis (Le et al., 2001; Caughey and Lansbury, 2003; D’Amore et al., 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 synapt…”
BackgroundMoechars, D., Lorent, K., & Leuven, F. V. (1999) · Neuroscience · doi:10.1016/s0306-4522(98)00599-5 · Cited by 69 · cited 3× · see citing works
“In contrast to many lines of mutant APP mice that exhibit a premature-death phenotype (Moechars et al., 1999b; Leissring et al., 2003), BRI-A 40 or BRI-A 42 mice did not have accelerated mortality (Fig.”
BackgroundResultDeng, Y., Tarassishin, L., Kallhoff, V., Peethumnongsin, E., Wu, L., Li, Y., & Zheng, H. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.5384-05.2006 · Cited by 64 · cited 1× · see citing works
“Small reductions in brain A 40 levels, with no change in A 42 levels, resulting from expression of an artificial exon 10 deletion mutant PSEN1 transgene were also associated with exacerbated amyloid plaque pathology in Tg2576 mice (Deng et al., 2006).”
BackgroundPresenilin/γ‐secretase activity regulates protein clearance from the endocytic recycling compartment
Zhang, M., Haapasalo, A., Kim, D. Y., Ingano, L. A. M., Pettingell, W. H., & Kovacs, D. M. (2006) · The FASEB Journal · doi:10.1096/fj.05-5531fje · Cited by 57 · cited 1× · see citing works
“In addition, mutations in PSEN can have a variety of effects on protein trafficking, clearance, and intracellular signaling (Koo and Kopan, 2004; Zhang et al., 2006).”
BackgroundDooren, T. V., Muyllaert, D., Borghgraef, P., Cresens, A., Devijver, H., der Auwera, I. V., Wera, S., Dewachter, I., & LEUVEN, F. V. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.050752 · Cited by 34 · cited 2× · see citing works
“…of A 40 to A 42 might promote the formation of CAA over parenchymal deposition (Herzig et al., 2004; Fryer and Holtzman, 2005; Fryer et al., 2005), in other studies, selective increases in A 42 were associated with more CAA (Van Dorpe et al., 2000; Samura et al., 2006; Van Dooren et al., 2006).”
ResultEnhanced accumulation of tau in doubly transgenic mice expressing mutant βAPP and presenilin-1
Samura, E., Shoji, M., Kawarabayashi, T., Sasaki, A., Matsubara, E., Murakami, T., Wuhua, X., Tamura, S., Ikeda, M., Ishiguro, K., et al. (2006) · Brain Research · doi:10.1016/j.brainres.2005.12.134 · Cited by 33 · cited 1× · see citing works
“…of A 40 to A 42 might promote the formation of CAA over parenchymal deposition (Herzig et al., 2004; Fryer and Holtzman, 2005; Fryer et al., 2005), in other studies, selective increases in A 42 were associated with more CAA (Van Dorpe et al., 2000; Samura et al., 2006; Van Dooren et al., 2006).”
ResultKrezowski, J. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh210 · Cited by 23 · cited 1× · see citing works
“Together, these studies provide indirect evidence that alterations in A levels can modulate the premature-death phenotype, although one study sug- gests that this is not because of A (Krezowski et al., 2004).”
BackgroundThe Bad Seed in Alzheimer’s Disease
Fryer, J. D., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.002 · Cited by 20 · cited 2× · see citing works
“In vivo, A 42 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).”
BackgroundResultKlein, W. L. (2004) · Neurobiology of Aging · doi:10.1016/s0197-4580(04)00089-2 · Cited by 18 · see citing works
Dorpe, J. A. V., Smeijers, L., Dewachter, I., Spittaels, K., den Haute, C. V., Tesseur, I. C., Sciot, R., & LEUVEN, F. V. (2000) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)82614-7 · Cited by 10 · see citing works
Kumar‐Singh, S., Theuns, J., Broeck, B. V., et al. (2006) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2006.05.1665
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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 · see citing works
“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 · see citing works
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 · see citing works
Self-citationReconsideration 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 · see citing works
“…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).”
BackgroundBasic mechanisms of neurodegeneration: a critical update
Jellinger, K. A. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01010.x · Cited by 608 · see citing works
Current state of Alzheimer’s fluid biomarkers
Molinuevo, J. L., Ayton, S., Batrla, R., Bednar, M. M., Bittner, T., Cummings, J., Fagan, A. M., Hampel, H., Mielke, M. M., Mikulskis, A., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1932-x · Cited by 518 · see citing works
Kuperstein, I., Broersen, K., Benilova, I., Rozenski, J., Jonckheere, W., Debulpaep, M., Vandersteen, A., Segers‐Nolten, I., Van Der Werf, K., Subramaniam, V., et al. (2010) · The EMBO Journal · doi:10.1038/emboj.2010.211 · Cited by 532 · see citing works
“Interesting in vivo studies have further shown that increased levels of Ab40 peptides in the brain actually might have a protective effect (Wang et al, 2006; Kim et al, 2007).”
BackgroundThe mechanism of γ‐Secretase dysfunction in familial Alzheimer disease
Chávez‐Gutiérrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.79 · Cited by 495 · see citing works
“Whereas A b 40 appears to act protectively in various toxicity assays (Wang et al , 2006; Kim et al , 2007), longer A b peptides promote aggregation and neurotoxicity (McGowan et al , 2005).”
Cheng, I. H.-J., Scearce-Levie, K. A., Legleiter, J. A., Palop, J. J., Gerstein, H., Bien‐Ly, N., Puolivaöli, J., Lesné, S., Ashe, K. H., Muchowski, P. J., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m701078200 · Cited by 403 · see citing works
Transgenic mouse models of Alzheimer’s disease.
Elder, G. A., Gama Sosa, M. A., & De Gasperi, R. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20159 · Cited by 336 · see citing works
Alzheimer's Aβ42 and Aβ40 peptides form interlaced amyloid fibrils
Gu, L., & Guo, Z. (2013) · Journal of Neurochemistry · doi:10.1111/jnc.12202 · Cited by 325 · see citing works
“Lowering Ab42/Ab40 ratios in transgenic mice decreases Ab deposition (Kim et al. 2007).”
Backgroundβ-Amyloid: the key peptide in the pathogenesis of Alzheimer’s disease
Sun, X., Chen, W., & Wang, Y. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00221 · Cited by 326 · see citing works
“There are two major isoforms of Aβ, soluble Aβ40, and insoluble Aβ42, and the latter peptide showing higher percentage concentration in AD patients is more prone to aggregate (Burdick et al., 1992; Gravina et al., 1995; Kim et al., 2007).”
BackgroundThe role of G protein-coupled receptors in the pathology of Alzheimer's disease
Thathiah, A., & De Strooper, B. (2011) · Nature Reviews Neuroscience · doi:10.1038/nrn2977 · Cited by 288 · see citing works
“42 ), the 40-amino acid isoform of amyloid-β that is anti-amyloidogenic in vivo”
BackgroundJan, A., Gokce, O., Luthi-Carter, R., & Lashuel, H. A. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803159200 · Cited by 291 · see citing works
Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies
Révész, T., Holton, J. L., Lashley, T., Plant, G. T., Frangione, B., Rostagno, A. A., & Ghiso, J. A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0501-8 · Cited by 293 · see citing works
“aggregation into amyloid both in vitro and in vivo [57, 76, 122].”
BackgroundPotent amyloidogenicity and pathogenicity of Aβ43
Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, N., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2858 · Cited by 280 · see citing works
Recent advances in our understanding of neurodegeneration
Jellinger, K. A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0240-y · Cited by 274 · see citing works
“This was shown in cellular models (Kumar-Singh et al. 2006) and in mouse models when increased levels of Ab-40 in brain while keeping the Ab-42 level decreased plaque burden (Kim et al. 2007).”
BackgroundKim, J., Castellano, J. M., Jiang, H., Basak, J. M., Parsadanian, M., Pham, V., Mason, S. M., Paul, S. M., & Holtzman, D. M. (2009) · Neuron · doi:10.1016/j.neuron.2009.11.013 · Cited by 274 · see citing works
Self-citationγ-Secretase inhibitors and modulators
Golde, T. E., Koo, E. H., Felsenstein, K. M., Osborne, B. A., & Miele, L. (2013) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2013.06.005 · Cited by 271 · see citing works
Self-citationMcAlpine, F. E., Lee, J., Harms, A. S., Ruhn, K. A., Blurton-Jones, M. M., Hong, J. J., Das, P., Golde, T. E., LaFerla, F. M., Oddo, S., et al. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.01.006 · Cited by 269 · see citing works
“…incubatef with mouse anti-human Aβ clone 6E10 (1:1000), rabbit anti-human Aβ40 (Chemicon, 1:100), mouse anti-Aβ40 (Mab 13.1.1, 1:500, (Das et al., 2003; Kim et al., 2007), rabbit anti-human Aβ42 (Invitrogen, 1:100), mouse anti-Aβ42 (Mab 2.1.3, 1:500, (Das et al., 2003; Kim et al., 2007), rabbit…”
InfluentialSelf-citationStructural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease
Pauwels, K., Williams, T. L., Morris, K. L., Jonckheere, W., Vandersteen, A., Kelly, G., Schymkowitz, J., Rousseau, F., Pastore, A., Serpell, L. C., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.264473 · Cited by 253 · see citing works
Amyloid-β as a Modulator of Synaptic Plasticity
Parihar, M. S., & Brewer, G. J. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101020 · Cited by 249 · see citing works
“ous [96].”
Mitochondrial Dysfunction as a Driver of Cognitive Impairment in Alzheimer’s Disease
Sharma, C., Kim, S., Nam, Y., Jung, U. J., & Kim, S. R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22094850 · Cited by 241 · see citing works
“For instance, a study of Aβ42-overexpressing BRI2-Aβ mice found no impairment in cognitive function or neurodegeneration despite the presence of Aβ oligomers and Aβ amyloid fibrils [9,10].”
BackgroundDysfunctional Mitochondria and Mitophagy as Drivers of Alzheimer’s Disease Pathogenesis
Chakravorty, A., Jetto, C. T., & Manjithaya, R. R. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00311 · Cited by 219 · see citing works
“In addition, later studies by Kim et al. (2007, 2013), using Aβ42 overexpressing BRI2-Aβ mice, showed that despite the presence of Aβ oligomers and Aβ amyloid fibrils, there was no impairment in cognitive function or degeneration of neurons.”
BackgroundRosenman, D. J., Connors, C. R., Chen, W., Wang, C., & Garcı́a, A. E. (2013) · Journal of Molecular Biology · doi:10.1016/j.jmb.2013.06.021 · Cited by 219 · see citing works
“Aβ40 and Aβ42 species demonstrate distinct mechanisms of oligomerization [8,9], and Aβ40 inhibits the aggregation of Aβ42 monomers in an Aβ42/Aβ40 ratio-dependent manner [10,11].”
Kiyota, T., Dixie, K. L. I., Swan, R. J., Jacobsen, M. T., Andrews, S. J., & Ikezu, T. (2011) · Gene Therapy · doi:10.1038/gt.2011.126 · Cited by 216 · see citing works
Multi-target design strategies for the improved treatment of Alzheimer's disease
Zhang, P., Xu, S., Zhu, Z., & Xu, J. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.05.020 · Cited by 218 · see citing works
“Aβ40 is the more common metabolite and may actually be anti-amyloidogenic, whereas Aβ42 and longer peptides are highly self-aggregating and lead to profound Aβ deposition [20].”
BackgroundCapsid Serotype and Timing of Injection Determines AAV Transduction in the Neonatal Mice Brain
Chakrabarty, P., Rosario, A. M., Cruz, P. E., Siemienski, Z. B., Ceballos‐Diaz, C., Crosby, K. W., Jansen, K. R., Borchelt, D., Kim, J., Jankowsky, J. L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0067680 · Cited by 201 · see citing works
Self-citationBifunctional Compounds for Controlling Metal-Mediated Aggregation of the Aβ<sub>42</sub>Peptide
Sharma, A. K., Pavlova, S. T., Kim, J., Finkelstein, D., Hawco, N. J., Rath, N. P., Kim, J., & Mirica, L. M. (2012) · Journal of the American Chemical Society · doi:10.1021/ja210588m · Cited by 202 · see citing works
Self-citationDesign of PLGA-functionalized quercetin nanoparticles for potential use in Alzheimer’s disease
Sun, D., Li, N., Zhang, W., Zhao, Z., Mou, Z., Huang, D., Liu, J., & Wang, W. (2016) · Colloids and Surfaces B Biointerfaces · doi:10.1016/j.colsurfb.2016.08.052 · Cited by 199 · see citing works
Imbimbo, B. P., & Giardina, G. A. M. (2011) · Current Topics in Medicinal Chemistry · doi:10.2174/156802611795860942 · Cited by 195 · see citing works
Systematic In Vivo Analysis of the Intrinsic Determinants of Amyloid β Pathogenicity
Luheshi, L. M., Tartaglia, G. G., Brorsson, A., Pawar, A. P., Watson, I. E., Chiti, F., Vendruscolo, M., Lomas, D. A., Dobson, C. M., & Crowther, D. C. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050290 · Cited by 186 · see citing works
“Furthermore, the longevity of these variants is comparable to that of flies expressing the Ab40 peptide (median survival ¼ 30 6 1d ; Figure S1A and S1B), which has been previously shown to be non-toxic when expressed both in transgenic flies [12,13] and in transgenic mice [ 17 ].”
BackgroundA <i>β</i> 42 and A <i>β</i> 40: similarities and differences
Qiu, T., Liu, Q., Chen, Y., Zhao, Y., & Li, Y. (2015) · Journal of Peptide Science · doi:10.1002/psc.2789 · Cited by 180 · see citing works
Hussien, H. M., Abd-Elmegied, A., Ghareeb, D. A., Hafez, H. S., Ahmed, H. E. A., & Moneam, N. M. A. E. (2017) · Food and Chemical Toxicology · doi:10.1016/j.fct.2017.11.025 · Cited by 176 · see citing works
Lashley, T., Holton, J. L., Gray, E., Kirkham, K., O’Sullivan, S. S., Hilbig, A., Wood, N. W., Lees, A. J., & Révész, T. (2008) · Acta Neuropathologica · doi:10.1007/s00401-007-0336-0 · Cited by 172 · see citing works
“In contrast, data from a recent transgenic animal study and other previous investigations indicate that A x–40 may have a possible protective role with a strong direct inhibitory eVect on Ax–42 aggregation into amyloid in vitro and amyloid deposition in vivo [ 22 , 40, 48].”
ResultInterleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice
Alves, S., Churlaud, G., Audrain, M., Michaelsen‐Preusse, K., Fol, R. R., Souchet, B., Braudeau, J., Körte, M., Klatzmann, D., & Cartier, N. (2016) · Brain · doi:10.1093/brain/aww330 · Cited by 172 · see citing works
Development and Mechanism of γ-Secretase Modulators for Alzheimer’s Disease
Crump, C. J., Johnson, D. S., & Li, Y. (2013) · Biochemistry · doi:10.1021/bi400377p · Cited by 173 · see citing works
Finder, V., Vodopivec, I., Nitsch, R., & Glockshuber, R. (2010) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.12.016 · Cited by 156 · see citing works
Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses
(2024) · aging and disease · doi:10.14336/ad.2023.0608 · Cited by 183 · see citing works
Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease: Current Evidence and Future Perspectives
McGrowder, D. A., Miller, F. G., Vaz, K., Nwokocha, C. R., Wilson-Clarke, C. F., Anderson, M., Brown, J., Anderson-Jackson, L., Williams, L., Latore, L., et al. (2021) · Brain Sciences · doi:10.3390/brainsci11020215 · Cited by 167 · see citing works
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158 · see citing works
“Of these two species, Ab42 is considered to be more amyloidogenic and thus more toxic (Aoki et al., 2008; Kim et al., 2007; McGowan et al., 2005).”
γ-Secretase Modulators as Potential Disease Modifying Anti-Alzheimer’s Drugs
Oehlrich, D., Berthelot, D., & Gijsen, H. J. M. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm101168r · Cited by 162 · see citing works
Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease
Szaruga, M., Veugelen, S., Benurwar, M., Lismont, S., Sepulveda-Falla, D., Lleo, A., Ryan, N. S., Lashley, T., Fox, N. C., Murayama, S., et al. (2015) · Journal of Experimental Medicine · doi:10.1084/jem.20150892 · Cited by 155 · see citing works
“Depletion of this particular peptide may also contribute to pathogenesis (Wang et al., 2006; Kim et al., 2007).”
BackgroundTauopathy with paired helical filaments in an aged chimpanzee
Rosen, R. F., Farberg, A. S., Gearing, M., Dooyema, J., M. Long, P., Anderson, D. C., Davis‐Turak, J., Coppola, G., Geschwind, D. H., Paré, J., et al. (2008) · Journal of Comparative Neurology · doi:10.1002/cne.21744 · Cited by 153 · see citing works
“The A 42:A 40 ratio, in particular, has been hypothesized to govern the risk of developing AD (Kim et al., 2007; McGowan et al., 2005), and soluble A oligomers are increasingly thought to play a crucial role (Catalano et al., 2006; Walsh and Selkoe, 2007).”
BackgroundKim, J., Yoon, H., Basak, J., & Kim, J. (2014) · Molecules and Cells · doi:10.14348/molcells.2014.0248 · Cited by 141 · see citing works
“A species, including the most abundant A40 and more toxic A42, are produced by two sequential proteolytic cleavages of amyloid precursor protein (APP) by and γ-secretases (Kim et al., 2007; McGowan et al., 2005).”
BackgroundSelf-citationCastellani, R. J., Lee, H., Siedlak, S. L., Nunomura, A., Hayashi, T., Nakamura, M., Zhu, X., Perry, G. L., & Smith, M. A. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-1151 · Cited by 140 · see citing works
“Aβ1−40 has been shown to be protective, thus targeting Aβ40 formation pharmacologically, or immunologically, could be deleterious [34].”
Becker, R. E., Greig, N. H., & Giacobini, E. (2008) · Journal of Alzheimer s Disease · doi:10.3233/jad-2008-15213 · Cited by 141 · see citing works
“posed the Aβ42/Aβ40 ratio as a predictive biomarker for AD [93,157].”
Gamma Secretase Modulators: New Alzheimer’s Drugs on the Horizon?
Bursavich, M. G., Harrison, B. A., & Blain, J. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01960 · Cited by 141 · see citing works
The effect of Cu2+ and Zn2+ on the Aβ42 peptide aggregation and cellular toxicity
Sharma, A. K., Pavlova, S. T., Kim, J., Kim, J., & Mirica, L. M. (2013) · Metallomics · doi:10.1039/c3mt00161j · Cited by 135 · see citing works
Self-citationCharacterization of Intermediate Steps in Amyloid Beta (Aβ) Production under Near-native Conditions
Olsson, F., Schmidt, S., Althoff, V., Munter, L. M., Jin, S., Rosqvist, S., Lendahl, U., Multhaup, G., & Lundkvist, J. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.498246 · Cited by 135 · see citing works
Amyloid β Protein: Aβ40 Inhibits Aβ42 Oligomerization
Murray, M. M., Bernstein, S. L., Nyugen, V., Condron, M. M., Teplow, D. B., & Bowers, M. T. (2009) · Journal of the American Chemical Society · doi:10.1021/ja8092604 · Cited by 128 · see citing works
Oddo, S., Caccamo, A., Tseng, B., Cheng, D., Vasilevko, V., Cribbs, D. H., & LaFerla, F. M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2464-08.2008 · Cited by 124 · see citing works
“In addition, these results indicate that A 40 is insufficient to trigger plaques formation, which is consistent with the data showing that A 42 is necessary for extracellular A formation (McGowan et al., 2005; Kim et al., 2007).”
The role of amyloid oligomers in neurodegenerative pathologies
Wells, C., Brennan, S. E., Keon, M., & Ooi, L. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.03.113 · Cited by 124 · see citing works
Rodent Aβ Modulates the Solubility and Distribution of Amyloid Deposits in Transgenic Mice
Jankowsky, J. L., Younkin, L. H., Gonzales, V., Fadale, D. J., Slunt, H. H., Lester, H. A., Younkin, S. G., & Borchelt, D. R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m611050200 · Cited by 122 · see citing works
Disease-Modifying Therapies for Alzheimer’s Disease: More Questions than Answers
Golde, T. E. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01201-2 · Cited by 119 · see citing works
Self-citationThe amyloid cascade and Alzheimer's disease therapeutics: theory versus observation
Castellani, R. J., Plascencia‐Villa, G., & Perry, G. L. (2019) · Laboratory Investigation · doi:10.1038/s41374-019-0231-z · Cited by 124 · see citing works
Zhang, Y., Rempel, D. L., Zhang, J., Sharma, A. K., Mirica, L. M., & Gross, M. L. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1309175110 · Cited by 118 · see citing works
Targeting Renin–Angiotensin System Against Alzheimer’s Disease
Gebre, A. K., Altaye, B. M., Atey, T. M., Tuem, K. B., & Berhe, D. F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00440 · Cited by 116 · see citing works
“ACE also metabolizes the most abundant amyloid peptide, Aβ40 with the potential to reduce the Aβ42 oligomerization and deposition (Kim et al., 2007; Murray et al., 2009).”
Backgroundγ-Secretase Substrate Concentration Modulates the Aβ42/Aβ40 Ratio
Yin, Y. I., Bassit, B., Zhu, L., Yang, X., Wang, C., & Li, Y. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m704601200 · Cited by 116 · see citing works
BRI2 (ITM2b) Inhibits A Deposition In Vivo
Kim, J., Miller, V. M., Levites, Y., West, K. J., Zwizinski, C. W., Moore, B. D., Troendle, F. J., Bann, M., Verbeeck, C., Price, R. W., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0891-08.2008 · Cited by 113 · see citing works
“4 m polyvinylidene fluoride membrane as previously described (Klug et al., 2003; Kim et al., 2007).”
BackgroundMethodResultInfluentialSelf-citationNikolic, W. V., Hou, H., Town, T., Zhu, Y., Giunta, B. N., Sanberg, C. D., Zeng, J., Luo, D., Ehrhart, J. C., Mori, T., et al. (2008) · Stem Cells and Development · doi:10.1089/scd.2008.0018 · Cited by 114 · see citing works
“For this analysis, we used the Tg2576 mouse model of AD, which is known to manifest copious A deposits in cerebral vessels at 15–20 months of age [35–39].”
Amyloid Cross-Seeding: Mechanism, Implication, and Inhibition
Subedi, S., Sasidharan, S., Nag, N., Saudagar, P., & Tripathi, T. (2022) · Molecules · doi:10.3390/molecules27061776 · Cited by 113 · see citing works
Koch, P., Tamboli, I. Y., Mertens, J., Wunderlich, P., Ladewig, J., Stüber, K., Esselmann, H., Wiltfang, J., Brüstle, O., & Walter, J. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.02.012 · Cited by 110 · see citing works
Philipson, O., Hammarström, P., Nilsson, K. P. R., Portelius, E., Olofsson, T., Ingelsson, M., Hyman, B. T., Blennow, K., Lannfelt, L., Kalimo, H., et al. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.022 · Cited by 106 · see citing works
“Indeed it has been shown that ncreased wtA 1-40 production can actually decrease amyoid plaque and CAA burden (Kim et al., 2007).”
BackgroundMolecular Dynamics Study of Zn(Aβ) and Zn(Aβ)2
Pan, L., & Patterson, J. C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0070681 · Cited by 101 · see citing works
“Also Ab(1-42) promotes amyloid deposition but Ab(1-40) inhibits the process [5].”
BackgroundAβ40 Protects Non-toxic Aβ42 Monomer from Aggregation
Yan, Y., & Wang, C. (2007) · Journal of Molecular Biology · doi:10.1016/j.jmb.2007.04.014 · Cited by 99 · see citing works
Behavior of neural stem cells in the Alzheimer brain
Waldau, B., & Shetty, A. K. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8053-y · Cited by 99 · see citing works
“There is also evidence in mouse models that Aβ40 inhibits amyloid deposition [32].”
BackgroundCellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
Mroczko, B., Groblewska, M., Litman-Zawadzka, A., Kornhuber, J., & Lewczuk, P. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19071884 · Cited by 97 · see citing works
Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?
Imbimbo, B. P., Panza, F., Frisardi, V., Solfrizzi, V., D’Onofrio, G., Logroscino, G., Seripa, D., & Pilotto, A. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.550572 · Cited by 96 · see citing works
“Recent studies in double transgenic mice have shown that Ab1 - 40 inhibits amyloid deposition while Ab1 - 42 increases it [114].”
BackgroundAnimal models of amyloid‐β‐related pathologies in Alzheimer’s disease
Philipson, O., Lord, A., Gumucio, A., O'Callaghan, P. W., Lannfelt, L., & Nilsson, L. N. G. (2010) · FEBS Journal · doi:10.1111/j.1742-4658.2010.07564.x · Cited by 98 · see citing works
Alzheimer's disease: Molecular aspects and treatment opportunities using herbal drugs
Thakral, S., Yadav, A., Singh, V., Kumar, M., Kumar, P., Narang, R., Sudhakar, K., Verma, A., Khalilullah, H., Jaremko, M., et al. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101960 · Cited by 99 · see citing works
Genetics of Alzheimer’s Disease
Ridge, P. G., Ebbert, M., & Kauwe, J. S. K. (2013) · BioMed Research International · doi:10.1155/2013/254954 · Cited by 96 · see citing works
Aβ40 promotes neuronal cell fate in neural progenitor cells
Chen, Y., & Dong, C. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2008.94 · Cited by 94 · see citing works
Targeting Aβ and tau in Alzheimer's disease, an early interim report
Golde, T. E., Petrucelli, L., & Lewis, J. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2009.07.035 · Cited by 89 · see citing works
“These peptides are hypothesized to behave like Aβ40 and inhibit Aβ42 aggregation (Kim et al., 2007), but this has not been tested in vivo.”
Self-citationShort Aβ peptides attenuate Aβ42 toxicity in vivo
Moore, B. D., Martin, J., de Mena, L., Sánchez, J., Cruz, P. E., Ceballos‐Diaz, C., Ladd, T. B., Ran, Y., Levites, Y., Kukar, T. L., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170600 · Cited by 89 · see citing works
“To examine whether Aβ38 expressed from rAAV vectors encoding BRI2-Aβ38 altered phenotypes in TgCRND8 mice, we expressed rAAV-BRI2-Aβ38, rAAV-BRI2-Aβ40, rAAV-BRI2-Stop, and rAAV-EGFP vectors from P0 to 9 mo in TgCRND8 mice and non-Tg (NTg) littermates.”
BackgroundMethodInfluentialSelf-citationAlzheimer’s disease – the journey of a healthy brain into organ failure
Golde, T. E. (2022) · Molecular Neurodegeneration · doi:10.1186/s13024-022-00523-1 · Cited by 90 · see citing works
Self-citationMechanism of Neuronal versus Endothelial Cell Uptake of Alzheimer's Disease Amyloid β Protein
Kandimalla, K. K., Scott, O. G., Fulzele, S., Davidson, M. W., & Poduslo, J. F. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004627 · Cited by 88 · see citing works
Placanica, L., Zhu, L., & Li, Y. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005088 · Cited by 88 · see citing works
Kim, S. H., Fraser, P. E., Westaway, D. A., George‐Hyslop, P. S., Ehrlich, M. E., & Gandy, S. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4717-09.2010 · Cited by 88 · see citing works
“This differential effect on A speciation was not anticipated but may well be important to pathogenesis and therapy, since one action of A 40 appears to be maintenance of A 42 solubility (Kim et al., 2007).”
Background(2012) · Progress in Molecular Biology and Translational Science · doi:10.1016/b978-0-12-385883-2.00006-0 · Cited by 84 · see citing works
Aβ solubility and deposition during AD progression and in APP × PS-1 knock-in mice
Murphy, M. P., Beckett, T. L., Ding, Q., Patel, E., Markesbery, W. R., Clair, D. K. S., LeVine, H., & Keller, J. N. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.06.002 · Cited by 85 · see citing works
Muratore, C., Zhou, C. Q., Liao, M., Fernandez, M. A., Taylor, W. M., Lagomarsino, V. N., Pearse, R. V., Rice, H. C., Negri, J. M., He, A., et al. (2017) · Stem Cell Reports · doi:10.1016/j.stemcr.2017.10.015 · Cited by 82 · see citing works
Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer's Disease Mice
Echeverrı́a, V., Zeitlin, R., Burgess, S., Patel, S. P., Barman, A., Thakur, G., Mamcarz, M., Wang, L., Sattelle, D. B., Kirschner, D. A., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-102136 · Cited by 82 · see citing works
Normal cognition in transgenic BRI2-Aβ mice
Kim, J., Chakrabarty, P., Hanna, A., March, A., Dickson, D. W., Borchelt, D. R., Golde, T., & Janus, C. (2013) · Molecular Neurodegeneration · doi:10.1186/1750-1326-8-15 · Cited by 83 · see citing works
“[24], which demonstrated the anti-amyloidogenic propensity of Aβ1-40 with respect to at least early stage amyloid deposition.”
BackgroundResultSelf-citationCurrent Biomarkers for Alzheimer’s Disease: From CSF to Blood
Zou, K., Abdullah, M., & Michikawa, M. (2020) · Journal of Personalized Medicine · doi:10.3390/jpm10030085 · Cited by 83 · see citing works
Alzheimer’s disease risk variants show association with cerebrospinal fluid amyloid beta
Kauwe, J. S. K., Wang, J., Mayo, K., Morris, J. C., Fagan, A. M., Holtzman, D. M., & Goate, A. M. (2009) · neurogenetics · doi:10.1007/s10048-008-0150-4 · Cited by 82 · see citing works
“total Aβ levels (driven by decreased Aβ40) are hypothesized to be associated with increased risk for AD [ 11 , 12].”
InfluentialImaging of cerebrovascular pathology in animal models of Alzheimer's disease
Klohs, J., Rudin, M., Shimshek, D. R., & Beckmann, N. (2014) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2014.00032 · Cited by 82 · see citing works
“Other reports suggested that Aβ40 can inhibit fibril formation and even inhibit amyloid deposition (Jarrett et al., 1993; Kim et al., 2007).”
BackgroundModulation of γ-secretase specificity using small molecule allosteric inhibitors
Shelton, C. C., Zhu, L., Chau, D.-M., Yang, L., Wang, R., Djaballah, H., Zheng, H., & Li, Y. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910757106 · Cited by 82 · see citing works
Alternative pathways for production of β-amyloid peptides of Alzheimer's disease
HOOK, V. Y. H., Schechter, I., Demuth, H., & Hook, G. (2008) · Biological Chemistry · doi:10.1515/bc.2008.124 · Cited by 82 · see citing works
“In contrast several studies recently clarified that Aβ 1-40 has neuroprotective functions (McGowan et al, 2005; Kim et al., 2007).”
BackgroundResultInfluentialThe value of incomplete mouse models of Alzheimer’s disease
Radde, R., Duma, C. C., Goedert, M., & Jucker, M. (2008) · European Journal of Nuclear Medicine and Molecular Imaging · doi:10.1007/s00259-007-0704-y · Cited by 81 · see citing works
“amyloid formation [33], and that expression of the amyloidogenic cystatin C inhibits Aβ amyloidosis [34], has led to the concept of amyloid interference, i.”
BackgroundAmyloid cross-seeding raises new dimensions to understanding of amyloidogenesis mechanism
Chaudhuri, P., Prajapati, K. P., Anand, B. G., Dubey, K., & Kar, K. (2019) · Ageing Research Reviews · doi:10.1016/j.arr.2019.100937 · Cited by 80 · see citing works
Cleavage of normal and pathological forms of α-synuclein by neurosin in vitro
Kasai, T., Tokuda, T., Yamaguchi, N., Watanabe, Y., Kametani, F., Nakagawa, M., & Mizuno, T. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.02.057 · Cited by 76 · see citing works
Coomaraswamy, J., Kilger, E., Wölfing, H., Schäfer, C., Kaeser, S. A., Wegenast‐Braun, B. M., Hefendehl, J. K., Wolburg, H., Mazzella, M. J., Ghiso, J. A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001056107 · Cited by 76 · see citing works
Zou, K., Maeda, T., Watanabe, A., Liu, J., Liu, S., Oba, R., Satoh, Y.-I., Komano, H., & Michikawa, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.011437 · Cited by 76 · see citing works
Tapia‐Rojas, C., Burgos, P. V., & Inestrosa, N. C. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13873 · Cited by 76 · see citing works
“It has been reported that Ab40 inhibits the aggregation of Ab42, decreasing the rate of aggregation (Frost et al. 2003; Yoshiike et al. 2003; Kim et al. 2007; Yan and Wang 2007).”
BackgroundVasilevko, V., Passos, G. F., Quiring, D., Head, E., Kim, R. C., Fisher, M., & Cribbs, D. H. (2010) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2010.05786.x · Cited by 72 · see citing works
“The pivotal role of Aβ42 in CAA formation was demonstrated in classical experiments by Todd Golde’s group using Tg mice selectively expressing only human Aβ40 or Aβ42 peptides in Bri-Aβ expressing cassette and crosses between those mice and Tg2576 [47,48].”
BackgroundComparison of Aβ levels in the brain of familial and sporadic Alzheimer's disease
Hellström‐Lindahl, E., Viitanen, M. H., & Marutle, A. (2009) · Neurochemistry International · doi:10.1016/j.neuint.2009.03.007 · Cited by 75 · see citing works
Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides
Stokin, G. B., Almenar-Queralt, A., Gunawardena, S., Rodrigues, E. M., Falzone, T., Kim, J., Lillo, C., Mount, S. L., Roberts, E. A., McGowan, E., et al. (2008) · Human Molecular Genetics · doi:10.1093/hmg/ddn240 · Cited by 72 · see citing works
Self-citationJin, Y., Li, F., Sonoustoun, B., Kondru, N. C., Martens, Y. A., Qiao, W., Heckman, M. G., Ikezu, T. C., Li, Z., Burgess, J. D., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-022-02421-8 · Cited by 69 · see citing works
Self-citationChang, Y., & Chen, Y. (2014) · FEBS Journal · doi:10.1111/febs.12813 · Cited by 68 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
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