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Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease
Open accessAbstract
The accumulation of amyloid β protein (Aβ) in the Tg2576 mouse model of Alzheimer's disease (AD) was evaluated by ELISA, immunoblotting, and immunocytochemistry. Changes in Aβ begin at 6–7 months as SDS-insoluble forms of Aβ42 and Aβ40 that require formic acid for solubilization appear. From 6 to 10 months, these insoluble forms increase exponentially. As insoluble Aβ appears, SDS-soluble Aβ decreases slightly, suggesting that it may be converting to an insoluble form. Our data indicate that it is full-length unmodified Aβ that accumulates initially in Tg2576 brain. SDS-resistant Aβ oligomers and most Aβ species that are N-terminally truncated or modified develop only in older Tg2576 mice, in which they are present at levels far lower than in human AD brain. Between 6 and 10 months, when SDS-insoluble Aβ42 and Aβ40 are easily detected in every animal, histopathology is minimal because only isolated Aβ cores can be identified. By 12 months, diffuse plaques are evident. From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted Aβ42 and Aβ40 increase to levels like those observed in AD brains. Coincident with the marked deposition of Aβ in brain, there is a decrease in CSF Aβ and a substantial, highly significant decrease in plasma Aβ. If a similar decline occurs in human plasma, it is possible that measurement of plasma Aβ may be useful as a premorbid biomarker for AD.
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TL;DR
In Tg2576 mice, formic acid-requiring Aβ42 and Aβ40 appear at 6–7 months and rise exponentially, while SDS-soluble Aβ declines slightly; plaques become evident later. As brain Aβ deposits, CSF and plasma Aβ decline, suggesting plasma Aβ may be a premorbid biomarker if a similar decline occurs in humans.
Key findings
- Formic acid-requiring Aβ42 and Aβ40 first appeared at ~7 months and were unequivocal by 8–9 months; between 6 and 12 months they increased exponentially and continued rising from 12 to 23 months to AD-like levels. SDS-soluble Aβ decreased slightly as insoluble Aβ appeared (Spearman: Aβ42 p = 0.02; Aβ40 p = 0.003; TBS/Triton fractions decreased, p = 0.009 for TBS Aβ42, TBS Aβ40, and Triton Aβ40; p = 0.05 for Triton Aβ42).
- Histopathology lagged biochemistry: at 6–10 months only isolated cored plaques were seen despite insoluble Aβ in every animal; diffuse plaques became evident by 12 months, and from 12–23 months diffuse plaques, neuritic plaques with cores, and extracted Aβ42/Aβ40 increased to levels like those in AD brain.
- In 21–23 month Tg2576 brain, only 5% of insoluble Aβ was N-terminally truncated or modified, versus 69–85% in AD brain; N3(pE) appeared late (16–23 months), and N11(pE) was not detected in Tg2576 but was detected in AD. Tg2576 initially accumulates full-length unmodified Aβ; oligomers and most modified forms appear only in older mice and at far lower levels than in AD.
- Coincident with brain deposition, CSF Aβ42 declined (p = 0.03 in text; Fig. 7 legend reports p = 0.02) and plasma Aβ42 and Aβ40 showed highly significant decreases (p = 0.008 and p = 0.006, respectively); nontransgenic littermates showed no decline, with a slight upward trend.
Methods
- Tg2576 mice and nontransgenic littermates were killed at 1–25 months; plasma was collected in 0.1% EDTA, CSF was obtained by the Carp method, and one hemibrain was frozen while the other was fixed.
- Brain was sequentially extracted by a four-step protocol (TBS, 1% Triton X-100, 2% SDS, 70% formic acid) or a two-step protocol (2% SDS then 70% formic acid); Aβ42/Aβ40 were measured by sandwich ELISA, immunoblotting, and immunocytochemistry using domain-specific antibodies.
- CSF/plasma sample sizes were Tg2576 CSF n = 45 and plasma n = 131 across age groups; nontransgenic CSF n = 10 and plasma n = 31. AD brains were stained in parallel (seven), and Table 2 AD groups were n = 6 with substantial congophilic angiopathy and n = 9 with minimal. Analyses included Spearman rank correlation and Mann-Whitney comparisons.
Limitations
- The paper has no formal limitations section; the authors state unresolved questions: why Tg2576 deposits large amounts of Aβ40, and whether the late development and relative paucity of modified or oligomeric Aβ reflects the shorter aggregation time or fundamental human/mouse biochemical differences.
- Evident: Tg2576 resembles the AD subgroup with Aβ40 predominance and congophilic angiopathy rather than most AD; only 5% of insoluble Aβ is N-terminally modified/truncated versus 69–85% in AD, N11(pE) is absent, and the authors mention minimal neurofibrillary pathology and neuronal loss in Tg2576 brain, limiting generalizability.
- Evident: SDS versus formic acid partitioning depends on extraction protocol (e.g., 21-month Tg2576: 66.2% SDS/33.1% FA four-step vs 10.6% SDS/89.4% FA two-step; AD: 81.5%/18.2% vs 13.8%/86.2%), so soluble/insoluble percentages are method-dependent. The plasma biomarker implication is explicitly conditional (“If a similar decline occurs in human plasma”).
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88 Own result · 24 No full text of the sources · 17 Own interpretation · 5 No basis given · 4 Partly supported · 4 Own method · 3 Supported · 2 Supported so far · 2 Not checked yet · 1 Sources not found · accuracy not yet measured
Every source the paper cites for this claim was checked and supports it.
In the paper
“In our previous study (Gravina et al., 1995), ELISAs for Ax-42 (BC-05/4G8) and Ax-40 (BA-27/4G8) showed that most of the A in AD brain is N-terminally truncated or modified.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
What the sources say
- Supportedcites Gravina et al., 1995 source
In the analysis of AD brains (page not supplied), the paper reports that the BC-05/4G8 and BA-27/4G8 ELISAs detected substantially more Aβ than assays requiring an intact N terminus. It interprets the difference as showing that much of the Aβ ending at either Aβ42(43) or Aβ40 is N-terminally truncated or modified, and elsewhere states that most Aβ in AD brains has that characteristic. (LLM, conf=0.90)
plainn = 27- Asserted: passes — The authors put it forward as true.
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In the paper
“In the 30% in which A40 was the predominant species deposited, there was typically prominent congophilic angiopathy.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
What the sources say
- Partly supportedcites Gravina et al., 1995 sourceExperimental — accuracy not yet measured
The Results report that Aβ40 was the major form deposited in six AD brains with substantial congophilic angiopathy. They do not establish the claimed 30% figure: those six were selected for separate analysis from a series of 27 brains, and the paper does not give a percentage of all cases in which Aβ40 predominated. (LLM, conf=0.88)
plaincorrelationaln = 27- Asserted: passes — The authors put it forward as true.
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In the paper
“and both forms continued to increase substantially from 12 to 23 months, reaching levels like those seen in the AD brain (Gravina et al., 1995).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > A that requires formic acid for extraction appears at 6-8 months in Tg2576 brain and increases with aging to a level like that seen in AD brain
What the sources say
- Partly supportedcites Gravina et al., 1995 sourceExperimental — accuracy not yet measured
The ‘Analysis of Aβ in 27 AD and 6 Plaque-free Control Brains’ section (page unavailable) measures formic-acid-requiring Aβ in AD brains, including forms ending at Aβ42(43) and Aβ40. It provides AD-brain levels as a reference, but does not study a 12-to-23-month increase or establish that the levels reached at 23 months were comparable to those in AD brain. (LLM, conf=0.86)
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The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Much of the A in AD brain is N-terminally truncated or modified (Saido et al., 1995(Saido et al., , 1996;;Hosoda et al., 1998)”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Saido et al., 1995 source
- Not checked — no full text of the sourcecites Saido et al., 1996 source
- Supportedcites Hosoda et al., 1998 source
The ELISA results (p. 4) report that N-terminally modified AβN3(pyroGlu)-42 had the highest average level among the measured Aβ species in AD frontal cortex. The Discussion (p. 6) likewise identifies it as a predominant species, supporting the claim that much of the Aβ in AD brain is N-terminally truncated or modified. (LLM, conf=0.92)
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“in which they are present at levels far lower than in human AD brain.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
“As insoluble A appears, SDS-soluble A decreases slightly”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“and a substantial, highly significant decrease in plasma A.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Our data indicate that it is full-length unmodified A that accumulates initially in Tg2576 brain.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“histopathology is minimal because only isolated A cores can be identified.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“By 12 months, diffuse plaques are evident.”
plain- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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- It may state two separate claims as one. 45
- Probably not a substantial claim. 26
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Thus, it appears that N-terminally modified or truncated forms of A, which predominate in AD brain (Saido et al., 1995(Saido et al., , 1996;;Hosoda et al., 1998), are minor species in Tg2576 brain that only begin to appear in very old mice.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
What the sources say
- Not checked — no full text of the sourcecites Saido et al., 1995 source
- Not checked — no full text of the sourcecites Saido et al., 1996 source
- Supportedcites Hosoda et al., 1998 source
The citation is attached to the statement that N-terminally modified or truncated Aβ forms predominate in AD brain. The Discussion (p. 6) identifies AβN3(pyroGlu)-42 and Aβx-42 as predominant species in AD frontal cortex; the statement about Tg2576 mice is the citing authors’ own conclusion, not a claim attributed to this paper. (LLM, conf=0.91)
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“In our previous examination of insoluble A in 27 AD brains (Gravina et al., 1995), A42 predominated in 70% and, in 33%, there was essentially no A40 deposited.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
What the sources say
- Partly supportedcites Gravina et al., 1995 sourceExperimental — accuracy not yet measured
The Abstract and the discussion of the 27-brain analysis report that virtually all Aβ ended at Aβ42(43) in 9 of 27 AD brains, supporting the approximately 33% with essentially no Aβ40 deposited. The discussion says Aβ40 was the major form in six cases, but it does not establish the claimed 70% figure for Aβ42 predominance across all 27 brains. (LLM, conf=0.82)
plainn = 27- Asserted: passes — The authors put it forward as true.
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- Partly supported
Every source the paper cites for this claim was checked and supports it.
In the paper
“In contrast, virtually all A terminated at A42 in the two AD brains examined (Fig. 5 K, L), as occurs in ϳ33% of AD cases (Gravina et al., 1995).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
What the sources say
- Supportedcites Gravina et al., 1995 source
The Abstract reports that in 9 of 27 AD brains—approximately 33%—virtually all Aβ (96%) ended at Aβ42(43). The citation supports the frequency stated in the citing sentence; the two brains shown in Fig. 5 are the citing paper’s own observation. (LLM, conf=0.91)
plainn = 2- Asserted: passes — The authors put it forward as true.
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In the paper
“and it has been suggested that the formation of SDS stable A oligomers may be an early event in AD (Enya et al., 1999).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Supportedcites Enya et al., 1999 source
The Discussion proposes that soluble SDS-stable Aβ dimers and oligomers may increase at the very initial stage of Aβ accumulation. It also suggests that deposition of SDS-stable dimers precedes deposition of SDS-dissociable Aβ, supporting the citing sentence’s hedged description of an early event in AD. Page numbers are not provided in our copy. (LLM, conf=0.91)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
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In the paper
“In most AD patients, very little A40 is deposited in the brain, but in ϳ33%, extraordinary amounts of A40 are deposited, and most of these patients show substantial amyloid angiopathy (Gravina et al., 1995).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Partly supportedcites Gravina et al., 1995 sourceExperimental — accuracy not yet measured
The Abstract and the analysis of 27 AD brains report that 9 of 27 had virtually no Aβ40, while the other 18 had increasing amounts. The paper links abundant Aβ40 with substantial angiopathy in six brains, but it does not establish that most patients deposited very little Aβ40 or that approximately 33% deposited extraordinary amounts. (LLM, conf=0.86)
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Partly supported
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In the paper
“From 12 to 23 months, diffuse plaques, neuritic plaques with amyloid cores, and biochemically extracted A42 and A40 increase to levels like those observed in AD brains.”
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SDS-resistant A oligomers and most A species that are N-terminally truncated or modified develop only in older Tg2576 mice”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“As shown in Figures 4 A-D and 5G, these oligomers are not detectable at 8 months but are definitely present by 12 months and increase substantially thereafter.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“They increased between 7 and 10 months but, even at 10 months, only a few cores were present in each section (Fig. 2 K, L).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Cored plaques appear early in Tg2576 brain
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The relevant percent-ages in 21 month Tg2576 are 66.2% SDS versus 33.1% FA with the four-step extraction and 10.6% SDS versus 89.4% FA with the two-step procedure”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The percentage of A in SDS and FA extracts of depositing Tg2576 and AD brain is influenced by the extraction procedure
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In these nontransgenic mice, there was no suggestion of a decline in A because A42 and A40 both showed a slight upward trend in CSF (Fig. 7G,H ) and plasma (Fig. 7 I, J ) with aging.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“SDS-insoluble 4 kDa A labeled by both BAN-50 (Fig. 4 B) and 4G8 (Fig. 4 D) appeared at 6 -8 months and increased substantially by 10 months.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“and in AD brains, 81.5% SDS versus 18.2% FA with four-step and 13.8% SDS versus 86.2% FA with two-step extraction.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The percentage of A in SDS and FA extracts of depositing Tg2576 and AD brain is influenced by the extraction procedure
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.
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In the paper
“In Tg2576 and AD brains, in which there is A deposition, the relative amounts of A extracted into SDS and FA with the two methods are considerably different.A much higher percentage of total A is extracted into SDS in the four-step method.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The percentage of A in SDS and FA extracts of depositing Tg2576 and AD brain is influenced by the extraction procedure
plaindirect- Asserted: passes — The authors put it forward as true.
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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
“In Tg2576 brains, diffuse plaques are not observed in appreciable number until 12 months, 4 months after biochemically detectable alterations in A have begun in every animal.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and it was accompanied by a decline in CSF A40, although this decrease did not achieve significance.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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In the paper
“The more sensitive sandwich ELISA assays (Fig. 1 H) were able to detect small amounts of SDS-extractable A in all systemic organs (10 -24 pmol/gm), but the amount of SDSextractable A in the brain was much larger (400 pmol/gm).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Human APP expression in Tg2576 mice is not confined to the brain
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Histochemical analysis (Fig. 6) showed that AN3-pyroglutamate (N3(pE)) appears late in Tg2576 brain, accumulating between 16 and 23 months.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > N-terminally modified As accumulate in aging Tg2576 brain
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, plasma A42 ( p ϭ 0.008) and A40 ( p ϭ 0.006) both showed highly significant decreases (Fig. 7 E, F ) that paralleled the marked accumulation of brain A and the decline in CSF A that occurred between 6 and 23 months.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: The Tg2576 transgenic mouse model is a valid model for studying human AD Aβ deposition.
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
“This indicates that, in Tg2576 brain, only 5% of insoluble A is N-terminally truncated or modified, whereas in AD brain, the corresponding percentage is 69 -85% (Table 2).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“This analysis confirmed that As terminating at both A40 and A42 accumulate in aging Tg2576 brain with A40 predominating (Figs. 2, 5 K, L).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The definite biochemical change that occurs by 10 months in Tg2576 mice is accompanied by minimal histological evidence of A deposition, although single plaque cores can be observed in many sections.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The total amounts of A42 and A40 extracted by two-step and four-step protocols are virtually identical, although slightly more A is extracted with the four-step method.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The percentage of A in SDS and FA extracts of depositing Tg2576 and AD brain is influenced by the extraction procedure
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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
“As insoluble (FA-requiring) A appears at 6 -9 months, the remaining A in the brain (SDS-extracted in two-step, or TBS-and Triton-extracted in four-step) decreases slightly”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > 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
“Similarly, in SDS extracts, BAN-50 labeled far more 4 kDa A in Tg2576 than in AD brains (Fig. 5A), whereas 4G8 labeled large amounts of A in both Tg2576 and AD brains (Fig. 5C).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, the unequivocal biochemical change that occurred between 6 and 10 months was accompanied by minimal immunocytochemical evidence of A deposition, although isolated, cored plaques were observed in virtually every section on careful inspection (Fig. 2).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > A that requires formic acid for extraction appears at 6-8 months in Tg2576 brain and increases with aging to a level like that seen in AD brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These early cored plaques were stained by Congo red and showed green birefringence with polarized light (data not shown).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Cored plaques appear early in Tg2576 brain
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Both meningeal and parenchymal blood vessels in the brain also showed progressive A accumulation.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Cored plaques appear early in Tg2576 brain
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moderate levels of transgenic human APP were present in Tg2576 heart, skin, bone, and muscle, and there was some human APP in pancreas, stomach, and large intestine (Fig. 1 D).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Human APP expression in Tg2576 mice is not confined to the brain
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Note that SDS-soluble A decreases transiently at 8 months, when SDS-resistant, formic acid-soluble A appears.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Our immunohistochemical and biochemical analyses show that, from 10 to 21 months, there is a rapid increase in both diffuse and cored plaques in Tg2576 brain and a coordinate marked increase in SDS-dissociable and FA-requiring A, with both the biochemical and histological changes rising to levels like those observed in human AD.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Significantly, plasma A is even higher in NOR 0304 (1400 pM A42; 5600 pM A40) than in Tg2576, but NOR 0304 mice do not develop age-dependent A deposition in brain.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The decline for CSF A42 is significant ( p ϭ 0.02), and the declines for plasma A40 and A42 are highly significant (A42, p ϭ 0.008; A40, p ϭ 0.006; Spearman's rank correlation for the 6 -23 month age range).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“After this early period, oligomers and most modified forms (e.g., forms beginning at 3pE) appear, but at levels far below those observed in AD brain.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This analysis showed that, coincident with the marked deposition of A42 and A40 in brain, there is not only a decline in CSF A but also a substantial, highly significant decrease in plasma A42 and A40.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
- Rests on an assumption: The Tg2576 transgenic mouse model is a valid model for studying human AD Aβ deposition.
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
“From 15 to 23 months ( C-H), A deposits increase in number and size and are detected both as cored plaques labeled by both BC-05 and BA-27 and as diffuse plaques, which are selectively labeled by BC-05.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Tg2576 mice, the APP K670N,M671L transgene is expressed at highest level in the brain, but there is also substantial expression in other organs (Fig. 1)”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The Tg2576 model is like this latter group of AD patients in that there is marked congophilic angiopathy and the deposition of a large amount of A40.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“If a similar decline occurs in human plasma, it is possible that measurement of plasma A may be useful as a premorbid biomarker for AD.”
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Amyloid  protein (A), the principal protein in the senile plaques of Alzheimer's disease (AD), is an ϳ4 kDa secreted polypeptide”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“They report that both SDSdissociable and -insoluble forms of A accumulate in human cortex”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Funato et al., 1998
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“From studies of trisomy 21 brains (Iwatsubo et al., 1994), it is generally believed that, in human AD, A deposition begins with the formation of diffuse plaques.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Iwatsubo et al., 1994 source
hedged- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“It is well established that this mutation causes concomitant increases in secreted A42 and A40 (Cai et al., 1993;Citron et al., 1994;Scheuner et al., 1996).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Thus, in all of these genetic forms of AD, A metabolism is altered in a way that fosters A aggregation and deposition.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
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.
None of the sources cited for this claim have been checked yet.
In the paper
“In addition, Tg2576 mice develop agedependent behavioral deficits as assessed by Y maze, T maze, and Morris water maze testing (Hsiao et al., 1996;Chapman et al., 1999;Westerman et al., 2000).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Sections from seven AD brains were stained in parallel.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Transgenic mice and e xtraction.
plainn = 7- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“each of these genetic forms of AD either selectively increases the extracellular concentration of A42 (Suzuki et al., 1994;Borchelt et al., 1996;Duff et al., 1996;Scheuner et al., 1996;Citron et al., 1997) or increases both A42 and A40 (Cai et al., 1993;Citron et al., 1994;Scheuner et al., 1996).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“It is well established that much of the A deposited as amyloid in AD brain is resistant to SDS extraction and requires formic acid for solubilization (Roher et al., 1993).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > A that requires formic acid for extraction appears at 6-8 months in Tg2576 brain and increases with aging to a level like that seen in AD brain
What the sources say
- Not checked — no full text of the sourcecites Roher et al., 1993 source
boosted- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“because CSF A, which has a high concentration relative to plasma A, is normally cleared into blood (Ghersi-Egea et al., 1996).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
What the sources say
- Not checked — no full text of the sourcecites Ghersi-Egea et al., 1996 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Secreted A is readily detected in CSF, plasma, and in medium conditioned by a wide variety of cultured cells”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“It is well established that A42 declines in the CSF of patients with typical late onset AD (Motter et al., 1995;Nitsch et al., 1995;Kanai et al., 1998;Andreasen et al., 1999)”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
What the sources say
boosted- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“there is good evidence that A1-42 is deposited early and selectively in senile plaques (Iwatsubo et al., 1994).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
- Not checked — no full text of the sourcecites Iwatsubo et al., 1994 source
boostedcorrelational- 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
“Synthetic A1-42 forms amyloid fibrils in vitro much more readily than A1-40 (Jarrett et al., 1993)”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
- Not checked — no full text of the sourcecites Jarrett et al., 1993 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.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Nontransgenic tissues were processed identically in parallel with the transgenic tissues.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Transgenic mice and e xtraction.
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.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Early onset Alzheimer's disease can be caused by mutations in the APP (Chartier-Harlin et al., 1991;Goate et al., 1991;Murrell et al., 1991;Mullan et al., 1992), presenilin 1 (PS1) (Sherrington et al., 1995), and presenilin 2 (PS2) (Levy-Lahad et al., 1995) genes.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Key words: Alzheimer's disease; neurodegeneration; Tg2576 transgenic animal model; amyloid  protein; cerebrospinal fluid; plasma
What the sources say
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
“They calculate that immunodetection of A in human cortex requires 400 pmol/gm insoluble A42 (or 200 pmol/gm in hippocampus) (Funato et al., 1998).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Funato et al., 1998
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“In a previous study of human plasma (Scheuner et al., 1996), we showed that the Swedish APP K670N,M671L mutation increases both A42 and A40 and that other FAD-linked APP, PS1, and PS2 mutations selectively increase A42.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Scheuner et al., 1996 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
In the paper
“and that its biochemical detection precedes plaque formation.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Funato et al., 1998
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“these modifications of A are thought to be important for amyloid deposition.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“We have shown recently that human plasma A42 and A40 increase with aging over age 65 and that plasma A42 and A40 are heritable traits that are increased in first degree relatives of patients with typical late onset AD (Younkin et al., 1998).”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not matchedcites Younkin et al., 1998
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
boosteddirect- 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 matched
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
“Because it is well established that CSF A42 decreases in AD, one way to account for these negative results is to postulate that plasma A42 also declines as AD develops.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgeddirect- Asserted: fails — The authors may not 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 authors may not put it forward as true. The paper’s conclusions may not depend on it.
In the paper
“that insoluble A correlates with amyloid load”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Funato et al., 1998
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“Thus, in Tg2576 mice as in human subjects, plasma A is likely to be derived from both peripheral organs and brain, where A may enter the bloodstream either through the normal flow of CSF or by directly crossing CNS endothelium.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Similarly, elevated plasma A could be an excellent premorbid biomarker for AD, although it is not useful as a diagnostic marker, if it identifies those who are destined to deposit A and those who are in the early stages of deposition.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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
“If this also occurs in human subjects, then declining plasma A could be a useful marker for subjects in whom there is cerebral A deposition and who are, therefore, at risk for AD.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“In that report, we suggested that cerebral A deposition in FAD occurs because of an increase in CNS A that develops as part of a generalized genetic effect that also increases plasma A.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
- Not checked — no full text of the sourcecites Scheuner et al., 1996 source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A claim is checked only against the cited paper’s full text, never its abstract, and none is available for its sources.
In the paper
“Because N-terminally truncated or modified A [especially forms beginning with pyroglutamate at position 3 (3pE)] and oligomers are resistant to proteolysis (Saido et al., 1996;Kuo et al., 1998)”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
What the sources say
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 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
“If so, then analysis of symptomatic late onset patients could miss many patients whose disease was initiated by increased A in the presymptomatic period.”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may state two separate claims as one.
The paper relies on this without support.
The human AD brain samples used for comparison are representative of Alzheimer's disease brain pathology.
“Sections from seven AD brains were stained in parallel.”
The paper relies on this without support.
N-terminal modifications or truncations of Aβ make Aβ more insoluble in human brain.
“which are thought to make A more insoluble in human brain”
The paper relies on this without support.
The Tg2576 transgenic mouse model is a valid model for studying human AD Aβ deposition.
“To determine whether CSF and plasma A decline in Tg2576 mice as A42 and A40 are deposited in the brain, we analyzed brain (Fig. 7 A, B), CSF (Fig. 7C, D), and plasma (Fig. 7 E, F ) A42 and A40 in parallel.”
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
“Tg2576 mice exhibit elevated Aβ from 2 months old onward, plaques after 6 months old, and cognitive deficits beginning at 5 months old [32,33,34].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [32]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > Compared with AD, Tg2576 brain has much less A that is truncated or modified at its N terminus
“Tg2576 21-23 months 5 A1-42 3409 Ϯ 64 26,076 A1-40 22,667 Ϯ 440 AX-42 1379 Ϯ 38 27,318 5%”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > The results obtained by sandwich ELISAs are confirmed by immunoblotting
“4G8 (anti-A17-24), which recognizes both full-length A and A that is N-terminally truncated or modified”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > CSF and plasma A decline as A is deposited in the Tg2576 brain
“This decline in CSF A42 ( p ϭ 0.03) occurred in parallel with the marked increases in brain A42 and A40”
§ Age-Dependent Changes in Brain, CSF, and Plasma Amyloid  Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease > DISCUSSION
“The decline for CSF A42 is significant ( p ϭ 0.02)”
Citations
Cites
Glenner, G. G., & Wong, C. W. (1984) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(84)80190-4 · Cited by 5,404
Goate, A., Chartier-Harlin, M.-C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., et al. (1991) · Nature · doi:10.1038/349704a0 · Cited by 4,659 · cited 2×
“Early onset Alzheimer’s disease can be caused by mutations in the APP (Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991; Mullan et al., 1992), presenilin 1 (PS1) (Sherrington et al., 1995), and presenilin 2 (PS2) (Levy-Lahad et al., 1995) genes.”
BackgroundThe precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619 · cited 2×
“Amyloid b protein (Ab), the principal protein in the senile plaques of Alzheimer’s disease (AD), is an ;4 kDa secreted polypeptide that is derived from several isoforms of a large protein referred to as the amyloid b protein precursor (bAPP) (Glenner and Wong, 1984; Masters et al., 1985; Kang et al., 1987 ).”
BackgroundAmyloid plaque core protein in Alzheimer disease and Down syndrome.
Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., & Beyreuther, K. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.12.4245 · Cited by 4,431 · cited 2×
“Amyloid b protein (Ab), the principal protein in the senile plaques of Alzheimer’s disease (AD), is an ;4 kDa secreted polypeptide that is derived from several isoforms of a large protein referred to as the amyloid b protein precursor (bAPP) (Glenner and Wong, 1984; Masters et al., 1985; Kang et al., 1987).”
BackgroundCorrelative 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 5×
“In addition, Tg2576 mice develop agedependent behavioral deficits as assessed by Y maze, T maze, and Morris water maze testing (Hsiao et al., 1996; Chapman et al., 1999; Westerman et al., 2000).”
BackgroundMethodInfluentialSelf-citationCloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease
Sherrington, R., Rogaev, E. I., Liang, Y., Rogaeva, E. A., Levesque, G., Ikeda, M., Chi, H., Lin, C., Li, G., Holman, K., et al. (1995) · Nature · doi:10.1038/375754a0 · Cited by 4,051 · cited 8×
“These findings suggest that, in typical late onset AD as in early onset FAD, elevated plasma Ab may be associated with the development of AD. If so, one would expect plasma Ab to be elevated in typical late onset AD. Our initial analysis of typical AD patients ( Scheuner et al., 1996 ) showed, however, that very few A…”
BackgroundInfluentialScheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599 · cited 5×
“In a previous study of human plasma (Scheuner et al., 1996), we showed that the Swedish APPK670N,M671L mutation increases both Ab42 and Ab40 and that other FAD-linked APP, PS1, and PS2 mutations selectively increase Ab42.”
BackgroundResultInfluentialSelf-citationJarrett, J. T., Berger, E. P., & Lansbury, P. T. (1993) · Biochemistry · doi:10.1021/bi00069a001 · Cited by 2,022 · cited 7×
“The following antibodies to Ab were used: monoclonal, BAN-50 (anti-Ab1–16), BA-27 (anti-Ab1–40), BC-05 (anti-Ab35–43), BNT-77 (anti-Ab11–28), 4G8 (anti-Ab17–24), and 6E10 (anti-Ab1–16); polyclonal, 3160 (anti-Ab1–40), Saeko (anti-C-terminal 30 amino acids of APP) (Kawarabayashi et al., 1996), and five antibodies descr…”
BackgroundInfluentialIwatsubo, T., Odaka, A., Suzuki, N., Mizusawa, H., Nukina, N., & Ihara, Y. (1994) · Neuron · doi:10.1016/0896-6273(94)90458-8 · Cited by 1,774 · cited 4×
“From studies of trisomy 21 brains ( Iwatsubo et al., 1994 ), it is generally believed that, in human AD, Ab deposition begins with the formation of diffuse plaques.”
BackgroundInfluentialMullan, M., Crawford, F., Axelman, K., Houlden, H., Lilius, L., Winblad, B., & Lannfelt, L. (1992) · Nature Genetics · doi:10.1038/ng0892-345 · Cited by 1,513 · cited 2×
“Early onset Alzheimer’s disease can be caused by mutations in the APP(Chartier-Harlin et al., 1991; Goate et al., 1991; Murrell et al., 1991; Mullan et al., 1992 ), presenilin 1 (PS1) (Sherrington et al., 1995), and presenilin 2 (PS2) (Levy-Lahad et al., 1995) genes.”
Background
Research works printed but not linked: 2
- Westerman, 2000, Age-dependent behavioral deficit in a transgenic mouse model of Alzheimer's disease., Soc Neurosci Abstr, 26, 1318
- Younkin, 1998, Genetic elevation of plasma amyloid β protein in typical late onset Alzheimer's disease., Soc Neurosci Abstr, 24, 263
Cited by
Sorted by citations
Items 601–700 of 1,063
Karlnoski, R., Rosenthal, A., Kobayashi, D. T., Pons, J., Alamed, J., Mercer, M., Li, Q., Gordon, M. N., Gottschall, P. E., & Morgan, D. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.4560-08.2009 · Cited by 34
“Most A requires SDS or formic acid for solubilization since the most abundant form of A at these ages are the insoluble, fibrillar forms (Kawarabayashi et al., 2001).”
BackgroundHarrison, F. E., May, J. M., & McDonald, M. P. (2009) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2009.11.009 · Cited by 34
Mixed Cerebrovascular Disease and the Future of Stroke Prevention
Fisher, M., Vasilevko, V., & Cribbs, D. H. (2012) · Translational Stroke Research · doi:10.1007/s12975-012-0185-6 · Cited by 37
“In 1999, Jucker and colleagues reported on their APP23 transgenic mice, which were generated with human APP751 with human double Swedish (Sw) mutation, which enhances β-secretase cleavage [43, 44].”
BackgroundThakker, D. R., Sankaranarayanan, S., Weatherspoon, M. R., Harrison, J., Pierdomenico, M., Heisel, J., Thompson, L. A., Haskell, R. J., Grace, J. E., Taylor, S. J., et al. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.2262-14.2015 · Cited by 32
“Tg2576 mice show robust levels of amyloid burden at 16 months of age (Kawarabayashi et al., 2001).”
BackgroundSubash, S., Essa, M. M., Al-Asmi, A. R., Al‐Adawi, S., & Vaishnav, R. (2014) · BioMed Research International · doi:10.1155/2014/546357 · Cited by 33
Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer's disease
Wang, J., Ferruzzi, M. G., Varghese, M., Qian, X., Cheng, A., Xie, M., Zhao, W., Ho, L., & Pasinetti, G. M. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-7 · Cited by 33
“In this specific mouse model of AD, the amyloid neuropathology was very aggressive and the amyloid content and plaque load at 6 months of age are equivalent to those found in old Tg2576 mice [7, 8 ].”
ResultLaursen, B., Mørk, A., Plath, N., Kristiansen, U., & Bastlund, J. F. (2013) · Brain Research · doi:10.1016/j.brainres.2013.10.055 · Cited by 33
Decock, M., Stanga, S., Octave, J., Dewachter, I., Smith, S. O., Constantinescu, S. N., & Kienlen‐Campard, P. (2016) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2016.00107 · Cited by 35
“Soluble oligomers have been characterized in transgenic mouse brains (Kawarabayashi et al., 2001; Lesne et al., 2006; Shankar et al., 2009; Pham et al., 2010), and to some extent in brains of AD patients (Hayden and Teplow, 2013).”
BackgroundSharma, H. S., Muresanu, D. F., Nozari, A., Lafuente, J. V., Tian, Z. R., Ozkızılcık, A., Manzhulo, I., Mössler, H., & Sharma, A. (2019) · Progress in brain research · doi:10.1016/bs.pbr.2019.03.009 · Cited by 33
Effect size of reference memory deficits in the Morris water maze in Tg2576 mice
Reed, M. N., Liu, P., Kotilinek, L., & Ashe, K. H. (2010) · Behavioural Brain Research · doi:10.1016/j.bbr.2010.03.037 · Cited by 35
“Mice were grouped into four age ranges [14] based on previously established changes in soluble Aβ oligomers [20], detergent-insoluble Aβ (Aβinsol) levels [25], and plaque pathology [4]: (1) very young mice, 4–5 months, after the appearance of Aβ trimers and hexamers but before the appearance of Aβinsol or plaques; (2)…”
Self-citationEmerging evidence for the neuroprotective role of α-synuclein
Lee, H., Zhu, X., Takeda, A., Perry, G. L., & Smith, M. A. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.04.024 · Cited by 37
Clinical Perspectives for the Use of Melatonin as a Chronobiotic and Cytoprotective Agent
Cardinali, D. P., Furio, A. M., & REYES, M. P. (2005) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1356.025 · Cited by 33
Homozygous carriers of APP A713T mutation in an autosomal dominant Alzheimer disease family
Conidi, M. E., Bernardi, L., Puccio, G., Smirne, N., Muraca, M. G., Curcio, S. A. M., Colao, R., Piscopo, P., Gallo, M., Anfossi, M., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001648 · Cited by 33
X11 rescues memory and long-term potentiation deficits in Alzheimer's disease APPswe Tg2576 mice
Mitchell, J. C., Ariff, B. B., Yates, D. M., Lau, K., Perkinton, M. S., Rogelj, B., Stephenson, J. D., Miller, C. C. J., & McLoughlin, D. M. (2009) · Human Molecular Genetics · doi:10.1093/hmg/ddp408 · Cited by 33
Dvir, E., Elman, A., Simmons, D. A., Shapiro, I., Duvdevani, R., Dahan, A., Hoffman, A., & Friedman, J. E. (2007) · CNS Drug Reviews · doi:10.1111/j.1527-3458.2007.00014.x · Cited by 33
“Moreover, brain function declines as Aß levels rise before plaques appear (Holcomb et al. 1998; Chapman et al. 1999; Moechars et al. 1999; Kawarabayashi et al. 2001; Pratico et al. 2001) and Aß accumulation in neurons has been associated with lysis events that result in plaque formation (D’Andrea…”
BackgroundEnhanced 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
Self-citationPathway-Specific Alteration of Synaptic Plasticity in Tg2576 Mice
Jung, J. H., An, K., Kwon, O. B., Kim, H.-S., & Kim, J. (2011) · Molecules and Cells · doi:10.1007/s10059-011-0077-8 · Cited by 33
“It is plausible that these older animals represent the more advanced stages of AD, but not the early stages that typically do not show neuronal loss (Kawarabayashi et al., 2001).”
BackgroundResultInfluentialSurala, M., Soso-Zdravkovic, L., Munro, D. A. D., Rifat, A., Ouk, K., Vida, I., Priller, J., & Madry, C. (2024) · EMBO Reports · doi:10.1038/s44319-024-00130-9 · Cited by 37
Milner, E., Zhou, M., Johnson, A. W., Vellimana, A. K., Greenberg, J. K., Holtzman, D. M., Han, B. H., & Zipfel, G. J. (2014) · Stroke · doi:10.1161/strokeaha.114.006078 · Cited by 33
Jung, C., Kato, R., Zhou, C., Abdelhamid, M., Shaaban, E. I. A., Yamashita, H., & Michikawa, M. (2022) · Scientific Reports · doi:10.1038/s41598-022-16626-0 · Cited by 36
Arachidonic acid diet attenuates brain Aβ deposition in Tg2576 mice
Hosono, T., Nishitsuji, K., Nakamura, T., Jung, C., Kontani, M., Tokuda, H., Kawashima, H., Kiso, Y., Suzuki, T., & Michikawa, M. (2015) · Brain Research · doi:10.1016/j.brainres.2015.04.005 · Cited by 32
“Between 15 and 23 months of age, Aβ deposition level in the Tg2576 brain increases with age, which is similarly observed in the AD brain (Kawarabayashi et al., 2001).”
BackgroundMethodInfluentialPlasma antibodies to Aβ40 and Aβ42 in patients with Alzheimer's disease and normal controls
Xu, W., Kawarabayashi, T., Matsubara, E., Deguchi, K., Murakami, T., Harigaya, Y., Ikeda, M., Amari, M., Kuwano, R., Abe, K., et al. (2008) · Brain Research · doi:10.1016/j.brainres.2008.02.060 · Cited by 32
Self-citationTargeting Insulin for Alzheimer’s Disease: Mechanisms, Status and Potential Directions
Lee, J. H., Jahrling, J. B., Denner, L. A., & Dineley, K. T. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-179923 · Cited by 36
Insights into Aβ and Presenilin from a Canine Model of Human Brain Aging
Head, E., & Torp, R. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0476 · Cited by 32
Mori, T., Maeda, J., Shimada, H., Higuchi, M., Shinotoh, H., Ueno, S., & Suhara, T. (2012) · Psychogeriatrics · doi:10.1111/j.1479-8301.2012.00409.x · Cited by 31
Pace, M. C., Xu, G. M., Fromholt, S., Howard, J. C., Crosby, K. W., Giasson, B. I., Lewis, J. M., & Borchelt, D. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1895-y · Cited by 31
“, SDS) is a wellknown criterion used to distinguish natively folded proteins from those that are misfolded and/or aggregated [32, 54, 64, 80, 91, 93].”
Transmission of cerebral amyloid pathology by peripheral administration of misfolded Aβ aggregates
Morales, R., Bravo-Alegria, J. B., Moreno‐González, I., Duran-Aniotz, C. A., Gamez, N., Edwards, G. A., & Soto, C. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01150-w · Cited by 31
Wu, G., Miller, R. A., Connolly, B., Marcus, J., Renger, J. J., & Savage, M. J. (2013) · Neurodegenerative Diseases · doi:10.1159/000353634 · Cited by 31
DNA base excision repair activities in mouse models of Alzheimer's disease
Weissman, L., de Souza-Pinto, N. C., Mattson, M. P., & Bohr, V. A. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.02.014 · Cited by 31
Cui, H., Hung, A. C., Klaver, D. W., Suzuki, T., Freeman, C. G., Narkowicz, C., Jacobson, G. A., & Small, D. H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023007 · Cited by 31
“However, the observation that C99 was present in higher abundance than C83 is consistent with some previous studies in both APP23 and Tg2576 mice [58,59,60].”
ResultInvestigation of Nebivolol as a Novel Therapeutic Agent for the Treatment of Alzheimer's Disease
Wang, J., Wright, H. M., Vempati, P., et al. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120904 · Cited by 31
“At this age, Tg2576 mice have already developed amyloid neuropathology [18] and mild cognitive impairments [19].”
BackgroundIntact spatial learning in adult Tg2576 mice
Bizon, J., Prescott, S., & Nicolle, M. M. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.01.004 · Cited by 23
Progress Update: Fluid and Imaging Biomarkers in Alzheimer’s Disease
Sutphen, C. L., Fagan, A. M., & Holtzman, D. M. (2014) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.07.031 · Cited by 31
“For example, in the Tg2576 APP transgenic mouse model, levels of CSF Aβ42 decrease as plaques begin to deposit in the brain (34).”
BackgroundParis, D., Ganey, N., Banasiak, M., Laporte, V., Patel, N., Mullan, M., Murphy, S. F., Yee, G.-T., Bachmeier, C., Ganey, C., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.2586-10.2010 · Cited by 30
“In old Tg APPsw brains (21–23 months), the total amount of A 40 and A 42 most closely resemble A levels in the AD brain and is 26,000 pmol/g (Kawarabayashi et al., 2001).”
BackgroundTargeting S100B in Cerebral Ischemia and in Alzheimer's Disease
Mori, T., Asano, T., & Town, T. (2010) · Cardiovascular Psychiatry and Neurology · doi:10.1155/2010/687067 · Cited by 31
“[128] T.”
BackgroundIncreased Aβ pathology in aged Tg2576 mice born to mothers fed a high fat diet
Nizari, S., Carare, R. O., & Hawkes, C. A. (2016) · Scientific Reports · doi:10.1038/srep21981 · Cited by 30
Michno, W., Wehrli, P. M., Meier, S. R., Sehlin, D., Syvänen, S., Zetterberg, H., Blennow, K., & Hanrieder, J. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14888 · Cited by 29
“…of the plaque over time, leading to formation of, e.g., diffuse or more densely packed, cored plaques (Nystrom et al. 2013, Rasmussen et al. 2017, Tycko 2015, Bitan et al. 2003) and how this relates to associated neurodegeneration and cognitive deficits (Kuo et al. 2001, Kawarabayashi et al. 2001).”
BackgroundResultInfluentialPérez‐Torres, C. J., Reynolds, J. O., & Pautler, R. G. (2013) · Magnetic Resonance in Medicine · doi:10.1002/mrm.24665 · Cited by 30
Watanabe, T., Iwasaki, K., Ishikane, S., Naitou, T., Yoshimitsu, Y., Yamagata, N., Özdemir, M. B., Takasaki, K., Egashira, N., Mishima, K., et al. (2008) · Journal of Pharmacological Sciences · doi:10.1254/jphs.fp0071648 · Cited by 31
Kim, T., Lee, J. E., Park, S. K., Lee, K.-W., Seo, J., Im, J., Kim, S., Lee, J., Kim, Y. H., Lee, J.-K., et al. (2012) · Experimental & Molecular Medicine · doi:10.3858/emm.2012.44.8.056 · Cited by 31
“Previous studies have reported that Aβ levels and plaque deposition in the brain of Tg2576 mice accumulate exponentially after visible plaques appear (Kawarabayashi et al., 2001; Flood et al., 2002; Lee et al., 2009), but the increase in Aβ levels follows a sigmoid growth path with a sub-saturation…”
BackgroundKurata, T., Miyazaki, K., Kozuki, M., Morimoto, N., Ohta, Y., Ikeda, Y., & Abe, K. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.09.030 · Cited by 31
Toxic oligomer species of amyloid-β in Alzheimer's disease, a timing issue
Lesné, S. (2014) · Swiss Medical Weekly · doi:10.4414/smw.2014.14021 · Cited by 36
Good, M. A., & Hale, G. (2007) · Behavioral Neuroscience · doi:10.1037/0735-7044.121.6.1180 · Cited by 22
Amylin in Alzheimer's disease: Pathological peptide or potential treatment?
Mietlicki‐Baase, E. G. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2017.12.016 · Cited by 30
“Earlier stages of the disease are characterized by higher levels of soluble oligomers and minimal presence of amyloid plaques; in contrast, plaques predominate in more advanced stages of AD (Kawarabayashi et al., 2001).”
BackgroundXu, G. M., Fromholt, S., Chakrabarty, P., Zhu, F., Liu, X., Pace, M. C., Koh, J., Golde, T. E., Levites, Y., Lewis, J. M., et al. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-00911-y · Cited by 29
Morales, R., Duran-Aniotz, C. A., Bravo-Alegria, J. B., Estrada, L. D., Shahnawaz, M., Hu, P., Kramm, C., Morales‐Scheihing, D., Urayama, A., & Soto, C. A. (2020) · Acta Neuropathologica Communications · doi:10.1186/s40478-020-01087-1 · Cited by 30
Alzheimer's disease amyloid-β pathology in the lens of the eye
Moncaster, J. A., Moir, R. D., Burton, M. A., Chadwick, O., Minaeva, O. V., Alvarez, V. E., Ericsson, M., Clark, J. I., McKee, A. C., Tanzi, R. E., et al. (2022) · Experimental Eye Research · doi:10.1016/j.exer.2022.108974 · Cited by 30
“…model was selected for this study because Tg + mice age-dependently express AD-related A β phenotypes and temporal progression of hA β molecular pathology that recapitulate the slow progression of amyloidopathy and cognitive deficits in human AD (Hsiao et al., 1996; Kawarabayashi et al., 2001).”
InfluentialMurphy, M., Wilson, Y. M., Vargas, E., Munro, K. M., Smith, B., Huang, A., Li, Q., Xiao, J., Masters, C. L., Reid, C. A., et al. (2014) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2014.09.014 · Cited by 29
“At this age, the Tg2576 mice have evidence of micro and macro amyloid deposits, in addition to higher levels of Ab compared with 6 months of age (Kawarabayashi et al., 2001).”
InfluentialMiddei, S., Daniele, S., Caprioli, A., Ghirardi, O., & Ammassari‐Teule, M. (2006) · Genes, Brain and Behavior · doi:10.1111/j.1601-183x.2005.00160.x · Cited by 27
“…we expected a selective disruption of hippocampaldependent operations in 7-month-old mutants evolving toward a more general cognitive impairment in 14-monthold mutants because of the development of a widespread amyloid burden (Hsiao et al. 1996; Irizarry et al. 1997; Kawarabayashi et al. 2001).”
BackgroundOue, H., Miyamoto, Y., Koretake, K., Okada, S., Doi, K., Jung, C., Michikawa, M., & Akagawa, Y. (2014) · Gerodontology · doi:10.1111/ger.12153 · Cited by 29
Poirier, G. L., Amin, E., Good, M. A., & Aggleton, J. P. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.11.025 · Cited by 30
“…mice (Hsiao et al., 1996), to examine the relationship of retrosplenial cortex dysfunction with βamyloid deposition and the widespread appearance of amyloid plaques, first seen in temporal regions in substantial numbers from 12 months in the brains of this mouse model (Kawarabayashi et al., 2001).”
BackgroundInfluentialColeman, R. A., Liang, C., Patel, R., Ali, S., & Mukherjee, J. (2017) · Molecular Imaging · doi:10.1177/1536012117704557 · Cited by 29
Dvir, E., Friedman, J. E., Lee, J. Y., Koh, J., Younis, F. M., Raz, S., Shapiro, I., Hoffman, A., Dahan, A., Rosenberg, G., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.103184 · Cited by 29
“SDS-soluble A protein samples were prepared as described previously (Kawarabayashi et al., 2001).”
MethodLIFESPAN DAILY LOCOMOTOR ACTIVITY RHYTHMS IN A MOUSE MODEL OF AMYLOID-INDUCED NEUROPATHOLOGY
Gorman, M. R., & Yellon, S. M. (2010) · Chronobiology International · doi:10.3109/07420528.2010.485711 · Cited by 27
“The first interval, from 16–23 weeks of age, was considered a young adult baseline, as animals at that time would be fully acclimated to the facility but not yet experiencing expected neuropathology and behavioral deficits that are generally minimal at that age (Kawarabayashi et al., 2001).”
BackgroundDíaz, A., Merino, P., Guo, J., Yepes, M., McCann, P., Katta, T., Tong, E. M., Torre, E. R., Rangaraju, S., & Yepes, M. (2020) · Journal of Neuroscience · doi:10.1523/jneurosci.2804-19.2020 · Cited by 29
“The predominant isoforms of the Ab peptide are Ab 1-40 and Ab 1-42 (Plant et al., 2003); and although in the early stages of AD both are soluble, at later stages insoluble forms are deposited into diffuse plaques (Kawarabayashi et al., 2001).”
BackgroundVulin, M., Zhong, Y., Maloney, B. J., Bauer, B., & Hartz, A. M. S. (2023) · Fluids and Barriers of the CNS · doi:10.1186/s12987-023-00470-z · Cited by 28
Shanthi, K. B., Krishnan, S., & Rani, P. (2015) · SAGE Open Medicine · doi:10.1177/2050312115598250 · Cited by 29
Martin, B. L., Tokheim, A. M., McCarthy, P. T., Doms, B. S., Davis, A. A., & Armitage, I. M. (2006) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-006-2390-7 · Cited by 28
“This strain of mice [34–39] expresses a mutant form of amyloid precursor protein, the so-called Swedish mutation, and share many of the behavioural difficulties associated with AD in humans.”
BackgroundWading pools, fading memories—place navigation in transgenic mouse models of Alzheimer's disease
Tanila, H. (2012) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2012.00011 · Cited by 28
“…in three different APP transgenic mouse lines: APP23 (APPswe under Thy-1 promoter, Van Dam et al., 2003), Tg2576 (APPswe under hamster PrP promoter, Kawarabayashi et al., 2001; Westerman et al., 2002), and APdE9 (APPswe and deletion of exon 9 of presenilin-1 under mouse PrP, Garcia-Alloza et al.,…”
BackgroundAβ N-terminal-end specific antibody reduced β-amyloid in Alzheimer-model mice
Horikoshi, Y., Mori, T., Maeda, M., Kinoshita, N., Sato, K., & Yamaguchi, H. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.10.039 · Cited by 27
Generation of amyloid β peptide with pyroglutamate at position 3 in primary cortical neurons
Shirotani, K., Tsubuki, S., Lee, H.-J., Maruyama, K., & Saido, T. C. (2002) · Neuroscience Letters · doi:10.1016/s0304-3940(02)00351-8 · Cited by 28
Self-citationAlcantara‐Gonzalez, D., Chartampila, E., Criscuolo, C., & Scharfman, H. E. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105274 · Cited by 25
Dodge, J. C., Tamsett, T. J., Treleaven, C. M., Taksir, T. V., Piepenhagen, P. A., Sardi, S. P., Cheng, S. H., & Shihabuddin, L. S. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00966-0 · Cited by 26
Lisgaras, C. P., & Scharfman, H. E. (2023) · Neurobiology of Disease · doi:10.1016/j.nbd.2023.106294 · Cited by 26
“Tg2576 transgenic mice show memory deficits at the age of 3 – 4 months (Duffy et al., 2015) and A β plaques by 6 – 12 months of age (Hsiao et al., 1996; Kawarabayashi et al., 2001; Ishii et al., 2014; Kam et al., 2016).”
BackgroundAlzheimer's disease biomarkers: correspondence between human studies and animal models
Sabbagh, J. J., Kinney, J. W., & Cummings, J. L. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.04.010 · Cited by 27
“aged Tg mice compared to non-Tg wild-type (WT) age-matched littermates (Kawarabayashi et al., 2001).”
BackgroundResultLuo, F., Rustay, N. R., Seifert, T. R., Roesner, B., Hradil, V. P., Hillen, H., Ebert, U., Severin, J. M., Cox, B. F., Llano, D. A., et al. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.172932 · Cited by 27
“It is possible that because of the high relative concentration of insoluble to soluble A in the brain of Tg2576 mice at older ages (Kawarabayashi et al., 2001) that the more selective antibody 8F5 demonstrated some nonspecific binding to fibrillar A and the vasculature.”
BackgroundQuan, L. N., Wu, J., Lane, L. A., Wang, J., Lu, Q., Gu, Z., & Wang, Y. (2016) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00019 · Cited by 27
Wang, X., Song, R., Lu, W., Liu, Z., Wang, L., Zhu, X., Liu, Y., Sun, Z., Li, J., & Li, X. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00157 · Cited by 27
“…of Aβ40 and Aβ42 peptides from soluble and insoluble fractions, we homogenized frozen cerebral hemispheres (150 mg/mL wet weight) in PBS containing 1% SDS with protease inhibitors (Roche), followed by centrifugation at 100,000 g for 60 min at 4◦C (Kawarabayashi et al., 2001; Vom Berg et al., 2012).”
MethodMaccarrone, M., Totaro, A., Leuti, A., Giacovazzo, G., Scipioni, L., Mango, D., Coccurello, R., Nisticò, R., & Oddi, S. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.02.009 · Cited by 27
Kim, J.-H., Jung, Y., Kim, J.-W., Ha, M., Ha, S.-M., & Kim, D. (2018) · Experimental Gerontology · doi:10.1016/j.exger.2018.03.024 · Cited by 28
Intramaze and Extramaze Cue Processing in Adult APPSWE Tg2576 Transgenic Mice.
Barnes, P., Hale, G., & Good, M. A. (2004) · Behavioral Neuroscience · doi:10.1037/0735-7044.118.6.1184 · Cited by 28
Dynamin 1 Regulates Amyloid Generation through Modulation of BACE-1
Zhu, L., Su, M., Lucast, L., Liu, L., Netzer, W. J., Gandy, S., & Cai, D. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045033 · Cited by 27
“Each frozen hemi-brain was then processed via step-wise solubilization [21,27].”
MethodKurata, T., Kawarabayashi, T., Murakami, T., Miyazaki, K., Morimoto, N., Ohta, Y., Takehisa, Y., Nagai, M., Ikeda, M., Matsubara, E., et al. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21352 · Cited by 26
“Overproduction of mutant bAPP in the mouse brain caused substantial Ab deposits (Hsiao et al., 1996; Kawarabayashi et al., 2001), with memory disturbance and subsequent typical pathological characteristics of AD.”
BackgroundSelf-citationImpact of common ALDH2 inactivating mutation and alcohol consumption on Alzheimer’s disease
Seike, T., Chen, C., & Mochly‐Rosen, D. (2023) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2023.1223977 · Cited by 28
“, 2002), Aβ accumulation from 9 to 12 months (Kawarabayashi et al., 2001), no tau phosphorylation (BilkeiGorzo, 2014), and no astrocyte activation (Kanamaru et al.”
BackgroundSarasa, L., Gallego, C., Monleón, I., Olvera, A., Canudas, J., Montañés, M., Pesini, P., & Sarasa, M. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.09.042 · Cited by 25
Höfling, C., Morawski, M., Zeitschel, U., Zanier, E. R., Moschke, K., Serdaroglu, A., Canneva, F., von Hörsten, S., Simoni, M. G. D., Forloni, G., et al. (2016) · Aging Cell · doi:10.1111/acel.12508 · Cited by 28
Latina, V., Caioli, S., Zona, C., Ciotti, M. T., Borreca, A., Calissano, P., & Amadoro, G. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00487 · Cited by 26
“…and are progressive (Pompl et al., 1999; King and Arendash, 2002; Kobayashi and Chen, 2005) although insoluble Aβ aggregates start to raise from 6 months (Kawarabayashi et al., 2001) and Aβ-laden plaque deposition is frankly detectable only at 11 months (Hsiao et al., 1996; Irizarry et al., 1997).”
BackgroundKimoto, A., Kasanuki, K., Kumagai, R., Shibata, N., Ichimiya, Y., & Arai, H. (2015) · Psychogeriatrics · doi:10.1111/psyg.12149 · Cited by 24
Age-dependent differential expression of BACE splice variants in brain regions of tg2576 mice
Zohar, O., Pick, C. G., Cavallaro, S., Chapman, J., Katzav, A., Milman, A., & Alkon, D. L. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.10.005 · Cited by 18
Aβ levels in serum, CSF and brain, and cognitive deficits in APP + PS1 transgenic mice
Liu, L., Tapiola, T., Herukka, S., Heikkilä, M., & Tanila, H. (2003) · Neuroreport · doi:10.1097/00001756-200301200-00030 · Cited by 24
Fulcher, J. M., Ives, A. N., Tasaki, S., Kelly, S. S., Williams, S., Fillmore, T., Zhou, M., Moore, R., Qian, W., Paša‐Tolić, L., et al. (2025) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2025.100983 · Cited by 25
“A “ gold standard ” approach for the plaque solubilization utilizes 70 to 100% FA (41 – 43).”
Lu, Y., Zhang, L., Nolan, C. E., Becker, S. L., Atchison, K. P., Robshaw, A., Pustilnik, L. R., Osgood, S. M., Miller, E. H., Stepan, A. F., et al. (2011) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.111.186791 · Cited by 25
Efficacy of SPI-1865, a novel gamma-secretase modulator, in multiple rodent models
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Animal Models of Alzheimer’s Disease
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“The present studies were carried out in 8–9-month-old Tg2576 mice and, although there is only very limited deposition of Ab visible as plaques at this age (Kawarabayashi et al., 2001), the accumulation of Ab is clearly measurable by biochemical analysis (DeMattos et al., 2002).”
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“Overexpression of these mutant genes in transgenic mice results in an age-dependent development of A fibril deposition (Hsiao et al., 1996; Kawarabayashi et al., 2001).”
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Aβ immunization: Moving Aβ peptide from brain to blood
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“Transgenic mice overexpressing APPSw (Tg2576) produce high levels of Ab and develop amyloid deposits (Kawarabayashi et al., 2001) but lack neurofibrillary tangles and, although gliosis and dystrophic neuritis are observed, do not suffer significant neuronal cell loss (Irizarry et al., 1997), in…”
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Metadata
- Authors
- Kawarabayashi, T., Younkin, L. H., Saido, T. C., Shoji, M., Ashe, K. H., & Younkin, S. G.
- Affiliations
- Mayo Clinic (US)
- Mayo Clinic in Florida (US)
- RIKEN (JP)
- Gunma University (JP)
- University of Minnesota (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-01-15
- Volume
- 21
- Issue
- 2
- Pages
- 372-381
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6763819
- OpenAlex
- W1929267935
- Semantic Scholar
- 3ed4c46400edeece515c7a23e469e89c233699f5
- Cited by
- 1,053
- References
- 38
- Citations by year
- 2026: 14 · 2025: 23 · 2024: 31 · 2023: 22 · 2022: 33 · 2021: 27 · 2020: 28 · 2019: 24 · 2018: 21 · 2017: 39 · 2016: 45 · 2015: 41 · 2014: 56 · 2013: 64 · 2012: 71
- FWCI
- 29.08
- 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
- National Institutes of Health
- National Institute on Aging (P01 AG015453, AG 15453)
- 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
- amyloid-beta, Alzheimer's disease, amyloid oligomers, amyloid plaques, neuritic plaques, cerebrospinal fluid amyloid, biomarkers, amyloid-beta 42, Aβ40
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Brain Chemistry, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Female, Formates, Humans, Immunohistochemistry, Male, Mice, Inbred C57BL, Mice, Transgenic, Organ Specificity, Sodium Dodecyl Sulfate, Immunoblotting, Biomarkers, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Plaque, Amyloid
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