On February 25, the Journal of Neuroscience quietly posted on its website its retraction of a 2011 paper that questioned the existence of Aβ aggregates inside neurons. In a terse statement, the journal, a publication of the Society for Neuroscience (SfN), cited “the journal’s findings of data misrepresentation” as the reason, and noted that it no longer considered the results of the study to be reliable. Unlike past retractions in the Alzheimer’s field, in this case the journal and the authors are publicly at odds. Senior authors Virginia Lee and John Trojanowski at the University of Pennsylvania Perelman School of Medicine in Philadelphia acknowledge mistakes in two figures. However, they assert that retraction was not necessary, as they believe the conclusions of the paper remain sound. An inquiry by UPenn supported their view. In addition, the authors said they have been banned from publishing in the journal for several years.

This issue has received coverage online, including in Retraction Watch, the blog DrugMonkey, and the Philadelphia Inquirer. Alzforum held off covering the retraction to give the Journal time to comment. For the first few days, representatives of J.Neurosci and SfN flatly declined, citing confidentiality, but later requested time to issue a general statement on standards of accuracy in the scientific literature, which was posted March 4.

At the time of its publication, the paper set off intense debate with its claim that commonly used anti-Aβ antibodies detected amyloid precursor protein (APP), rather than Aβ, inside neurons of 3xTg AD mice. In essence, the authors asserted that the finding of intraneuronal Aβ had been an artifact. The result challenged a previous paper by Frank LaFerla and colleagues at the University of California, Irvine, which had reported extensive intraneuronal Aβ accumulation in these mice (see Oddo et al., 2003, and Nov 2002 Webinar). Alzforum covered the issue in a June 2011 Webinar, which featured vigorous debate and was followed by spirited written commentary for some weeks.

Has time and more research told whether the paper was right? Not really. While some studies published since 2011 agree with Lee and Trojanowski that APP, or longer fragments of it, makes up the bulk of intraneuronal amyloid staining, most papers also report at least low levels of Aβ inside cells. Other recent papers flag intraneuronal Aβ as a key culprit in damaging neurons and synapses. “I think most researchers acknowledge the existence of intraneuronal Aβ aggregates as a pathologic feature, but still question its pathogenic relevance,” Lars Nilsson at Oslo University, Norway, wrote to Alzforum.

Now the retraction of the 2011 paper adds another wrinkle to an already complicated story. It is unclear what first drew the journal’s scrutiny. Citing confidentiality, SfN and journal staff declined to say whether they routinely check for image manipulation, or whether someone inside or outside the journal raised a flag. Some journals use automated software to detect problems with figures. Such an analysis likely would have turned up the errors. In this paper, they amounted to three instances of a duplicated image being used to represent different data. Specifically, panels E and F of Figure 1, and panels E and H, as well as F and G, in Figure 4, depict the same microscopic field, in some cases rotated or shown at different magnifications, even though the captions identified the images as coming from mice of different ages and showing progression. Lee said she first became aware of the issue in February 2014, when she received a letter from the SfN Ethics Committee pointing out the image duplications.

The committee also informed the Perelman School of Medicine. The school conducted a preliminary inquiry, which is standard procedure in such cases, executive vice dean Glen Gaulton told Alzforum. The inquiry committee examined lab notebooks and raw data and interviewed the authors, including first author Matthew Winton, who left research in 2008 and now works as a financial consultant for a pharmaceutical company in the Boston area. According to Gaulton, Winton acknowledged making mistakes in image selection during revisions on the paper. Gaulton noted that an earlier, draft version of the paper contained the correct images. Winton did not respond to Alzforum’s emailed requests for comment. The UPenn committee concluded that the mistakes were unintentional and did not alter the findings of the paper. Gaulton said they reported this to the SfN Ethics Committee in a letter published by Retraction Watch. Lee said she offered to submit a correction to the journal, but was informed last month that it would retract the paper instead.

While SfN’s statement does not directly discuss the incident, it notes that “[SfN policies] address the ethical responsibility of principal investigators, among all authors; highlight that violations may or may not involve any intent to mislead; and encourage the practice of proactive and prompt correction or retraction by authors when an issue becomes evident.” Peggy Mason of the University of Chicago chairs SfN’s ethics committee. She shared her views on data integrity with Alzforum, though she stressed that her opinions do not necessarily represent those of the society. “The ethics committee’s primary goal is to defend the scientific literature. If there are errors in the details of a paper that make it no longer trustable, it needs to be retracted,” Mason said. She noted that this is true regardless of whether or not the errors were intentional. In cases of a single small error, a correction might be appropriate instead, she added. Mason said that ethics committees have a secondary mission to try to prevent the recurrence of problems; to accomplish this, these institutions sometimes impose punitive measures, such as publishing bans.

Researchers in the field expressed surprise at the events and the penalty. They agreed the mistakes were unlikely to be intentional. “If you wanted to misrepresent results, you wouldn’t do it by duplicating figures,” Charlie Glabe at UC Irvine wrote in an email. Nilsson concurred that the errors leave the paper’s conclusions intact, but noted that retraction could still be justified. “As a reader, you need to trust that images shown are correct as described,” he wrote to Alzforum.

What about the central claim that neurons in the triple transgenic mice accumulate APP, not Aβ? Of this, scientists were more skeptical. They note that it is difficult to prove something is not there, because it is always possible the methods used were not sensitive enough to detect it. Several groups since have analyzed the triple transgenic mice and similar models using a variety of methods, and reported the presence of at least some intraneuronal Aβ. For example, Mary Jo LaDu and Leon Tai at the University of Illinois, Chicago, developed the MOAB-2 antibody, which they report recognizes the N-terminal end of Aβ and does not cross-react with APP. This antibody lit up neurons in both triple transgenic and 5xFAD mice brains, they found (see Youmans et al., 2012). However, common anti-Aβ antibodies such as 6E10 and 4G8 cross-react with APP and should not be used to measure Aβ, LaDu told Alzforum.

Likewise, Thomas Bayer and Oliver Wirths at Georg-August-University Göttingen, Germany, used conformation-specific antibodies to detect intraneuronal Aβ in the triple transgenics, although they report that most of it occurs in the cortex, with low levels in hippocampus (see Wirths et al., 2012). Researchers led by Claudio Cuello at McGill University, Montreal, took a different tack, employing high-resolution microscopy, mass spectrometry analysis, and ELISAs to determine that Aβ accumulates inside neurons of a transgenic rat model (see Iulita et al., 2014).

While this recent work contradicts the contention that Aβ does not accumulate inside neurons, several of the papers, including those of Bayer and Wirths and LaDu and Tai, did replicate Lee and Trojanowski’s finding of large amounts of intraneuronal APP in the triple transgenics. Researchers led by Frédéric Checler at the CNRS in Valbonne, France, added a different twist, suggesting that most of the intraneuronal amyloid immunoreactivity in this model comes from the C99 fragment of APP. Intraneuronal Aβ appears only late in life in the triples, the authors reported (see Lauritzen et al., 2012).

Bayer and Wirths summarized the findings from the 3xTg mice in an email to Alzforum, writing, “The main immunostaining detected by pan-Aβ antibodies is due to APP cross-reactivity. The age-dependent APP accumulation in the 3xTg model is unique and has not been observed in other APP transgenic mouse models, at least to our knowledge.” (See full comment below.)

This intraneuronal APP may contribute to pathology, Glabe noted. “It is pathologically misfolded, insoluble and aggregated, in the same fashion as it ends up in plaques,” he wrote. “You see the same type of intraneuronal immunoreactivity in human brain. It just means that not all of the amyloid that accumulates comes from the BACE1/γ-secretase pathway that makes secreted Aβ40 and Aβ42.”

Human studies have been slow to add evidence for a role for intraneuronal Aβ. In the March 1 Brain, researchers led by Changiz Geula at Northwestern University, Chicago, report seeing Aβ inside basal forebrain cholinergic neurons in people even as young as 20. While its quantity stayed unchanged with age or Alzheimer’s disease, more of it became aggregated into oligomers and larger species, they believe. Because other types of neurons did not accumulate Aβ, the finding might provide a clue to the selective degeneration of cholinergic neurons in AD, the authors suggest (see Baker-Nigh et al., 2015).

Gunnar Gouras at Lund University, Sweden, told Alzforum, “The Winton et al. paper certainly put a damper on the topic of intraneuronal Aβ, but it did not stop research in this area, which has grown at conferences and in papers.”—Madolyn Bowman Rogers

Comments

  1. Whether intraneuronal Aβ peptides play a (key) role in the etiology of Alzheimer’s disease (AD) is still a matter of scientific debate. Since the initial publication in 2003, the 3xTg mouse model  (Oddo et al., 2003) has attracted considerable attention in the scientific community, as it apparently would support the hypothesis that intraneuronal Aβ might trigger synaptic degeneration, as well as amyloid plaque and neurofibrillary tangle formation.

    The presence of intraneuronal Aβ peptides and their relevance in human postmortem AD tissue was, however, challenged. This is in part due to variations in immunohistochemical staining protocols, as well as in the use of antibodies that are commonly unable to discriminate between Aβ and its precursor APP, such as 4G8 or 6E10 (Aho et al., 2010). 

    A variety of transgenic AD mice have been developed over the last 20 years, and intraneuronal Aβ accumulation has been reported in a multitude of models by various groups without any doubt (reviewed in Wirths and Bayer, 2012). Therefore animal models have had a great impact on the concept of intraneuronal Aβ. On the other hand, some findings were slightly over-interpreted.

    Due to the importance of the 3xTg mouse model, we, like Winton et al. (2011), took a closer look at the occurrence of intraneuronal Aβ (Wirths et al., 2012). We were able to confirm the main conclusion that aberrant APP accumulation accounts for the majority of the immunoreactivity detected by antibodies harboring central epitopes like 4G8 or 6E10. APP accumulates within neurons in an age-dependent manner, which might be in part due to the fact that concomitant overexpression of mutant Tau leads to axonal transport alterations resulting in APP mistrafficking. We were, however, also able to confirm the age-dependent accumulation of intraneuronal Aβ peptides in the 3xTg model. This was mainly found in cortex and subiculum, as demonstrated by the use of conformation-specific antibodies or antibodies detecting neo-epitopes generated by APP cleavage. We did not detect abundant amounts of Aβ in the hippocampus, which is in contrast to the initial report. In this respect it is interesting to note that Lauritzen and colleagues reported a strong accumulation of the β-cleaved APP C-terminal fragment C99 in the hippocampus but not the cortex in the 3xTg mouse model, identifying C99 as the main contributor to APP-related immunoreactivity (Lauritzen et al., 2012).

    In summary, the errors in the Winton paper do not invalidate the general conclusions of the original paper. While it is also true that we could not confirm the complete absence of intraneuronal Aβ in the 3xTg model, the main immunostaining detected by pan-Aβ antibodies is due to APP cross-reactivity. The age-dependent APP accumulation in the 3xTg model is unique and has not been observed in other APP transgenic mouse models—at least to our knowledge.

    References:

    . Immunohistochemical visualization of amyloid-beta protein precursor and amyloid-beta in extra- and intracellular compartments in the human brain. J Alzheimers Dis. 2010;20(4):1015-28. PubMed.

    . The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci. 2012 Nov 14;32(46):16243-55a. PubMed.

    . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.

    . Intraneuronal Aβ accumulation and neurodegeneration: Lessons from transgenic models. Life Sci. 2012 Feb 26; PubMed.

    . AβPP Accumulation and/or Intraneuronal Amyloid-β Accumulation? The 3xTg-AD Mouse Model Revisited. J Alzheimers Dis. 2012 Jan 1;28(4):897-904. PubMed.

    . Intraneuronal APP, not free Aβ peptides in 3xTg-AD mice: implications for tau versus Aβ-mediated Alzheimer neurodegeneration. J Neurosci. 2011 May 25;31(21):7691-9. PubMed.

  2. The major point made by Winton et al. was that many of the antibodies raised against Aβ also crossreact with APP and other APP fragments, not that intracellular Aβ does not exist in the transgenic mice at all. Besides, Aβ deposition, which precedes disease onset by approximately 25 years in human cases, cannot be directly toxic alone without tauopathy. Retraction appears too harsh: Nature, Cell and Science have published so many papers that should be retracted.

  3. If Winton et al. had reported on accumulation of APP in the triple transgenic there would not have been such a reaction. But the paper and the Alzforum webinar questioned the whole area of intraneuronal Aβ. Many in the field thought this was going too far. I have not done the careful comparison among many different AD transgenics as Bayer and Wirths have, and it is interesting that the triple transgenics have more APP accumulation than other lines. The problem with Winton et al. was the focus on absence of intraneuronal Aβ. Most investigators see some intraneuronal Aβ in the triples. By Western blot the triple transgenics were shown to accumulate Aβ, and one has to remember that even neurons in normal brain have intraneuronal Aβ. Aβ is normally made within neurons, as Dennis Selkoe pointed out in his 2011 comment to Winton et al.

    Even in human AD brain there is aberrant APP accumulation. It has been known for decades that dystrophic neurites in AD accumulate APP. Charlie Glabe published an interesting hypothesis some years back suggesting that aggregating APP might be quite important early in AD. This is just to suggest that having APP accumulation does not discredit the triple transgenics as a model of AD.

    I knew nothing about this J Neurosci investigation but can’t help but wonder if the journal's decision might have been influenced by Winton et al.’s insistence about there not being any intraneuronal Aβ. Yet, I agree with Charlie and Lars that the issues with the paper were unintentional and that the senior investigators of this study remain admired neuroscientists who have contributed so much to our field.

    Finally, I want to comment on the note in the current story that “Human studies have been slow to add evidence for a role for intraneuronal Aβ”. In fact, human studies preceded animal studies and without them I would be less convinced that intraneuronal Aβ is important in AD. While detecting intraneuronal Aβ in brain can indeed be challenging by standard light microscopy, higher resolution imaging such as EM show that this pool of Aβ is significant. When appropriate aggregation-specific antibodies are used, it becomes even more remarkable.

    References:

    . Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer's disease. J Mol Neurosci. 2001 Oct;17(2):137-45. PubMed.

    . Intraneuronal abeta-amyloid precedes development of amyloid plaques in Down syndrome. Arch Pathol Lab Med. 2001 Apr;125(4):489-92. PubMed.

    . Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5):1869-79. PubMed.

    . Intraneuronal Abeta42 accumulation in Down syndrome brain. Amyloid. 2002 Jun;9(2):88-102. PubMed.

    . Immunohistochemical visualization of amyloid-beta protein precursor and amyloid-beta in extra- and intracellular compartments in the human brain. J Alzheimers Dis. 2010;20(4):1015-28. PubMed.

    . Analysis of microdissected human neurons by a sensitive ELISA reveals a correlation between elevated intracellular concentrations of Abeta42 and Alzheimer's disease neuropathology. Acta Neuropathol. 2010 May;119(5):543-54. PubMed.

  4. Arguing about whether it is Aβ40, Aβ42 or not is missing the important point: It is aggregated in an amyloid-like fashion, because it reacts with a large number of antibodies that only react with aggregated or fibrillar conformations. If it is aggregated Aβ43, Aβ46, Aβ49 or Aβ99—it is inconsequential? Whether it is aggregated is more important than how short it is.

  5. In our view, Winton et al. never should have published this paper, because the methodology—as used by the authors—is inadequate for discerning between the presence of cleaved APP fragments and the presence of full-length APP. The resolution of all images shown in the paper does not allow identification of distinct immunostaining patterns for the various APP epitopes, if such patterns exist. Localization of stained epitopes to defined subcellular compartments cannot be seen in the presented images. The micrographs show nothing more that tiny neuronal somas entirely stained by the antibodies. At the provided resolution, the dual labeling of epitopes from the N- or C-terminal domains, and from the Aβ region, of APP does not reveal whether the two epitopes are part of full length APP, or of cleaved fragments. Indeed, the cleaved fragments may very well co-localize in some compartments, rendering conclusions difficult to draw. In the images provided, the immunolabeling covers the entire soma, irrespective of the antibodies used. Immunolabeling of any abundant household protein would not look any different than these images.

    If one considers carefully the images in Fig. 5, this paper would actually argue for the intraneuronal cleavage of APP and significant accumulation of Aβ inside neurons in the triple transgenic mouse.  Although there are indeed yellow-stained somas in the “merge” images, there are also many somas that stain either green (indicative of Aβ or N-terminal epitopes) or red (C-terminal epitopes).  If only full-length APP was present in these neurons, the green/red ratio should have been the same in all cells.  It is not.  What stronger evidence supporting the presence of neurons that contain cleaved APP fragments (including Aβ) inside the soma would one want?

    Fig. 6 is the only one that could indicate that there is no Aβ in the cells stained with the C-terminal antibody, 5685.  However, these images can’t be properly evaluated in the absence of a positive, internal control.  Since the triple transgenic mouse develops plaques, plaque-containing regions with strong anti-Aβ staining should have been shown here.  In addition, the micrographs showing staining with antibodies to Aβ (middle images) are completely black.  Not even a hint of autofluorescence.  That to us sounds quite unbelievable, as there is almost always a little bit of background staining.

    In conclusion, to us, the data in the Winton et al. paper actually argues strongly for the presence of intraneuronal Aβ in the triple transgenic mouse.  Yet this paper unquestionably put a brake on studies investigating the mechanisms of accumulation of intraneuronal Aβ in Alzheimer’s disease.  We wonder how many papers reporting on intraneuronal Aβ, and how many grant applications on this topic, were deemed irrelevant based at least in part on the conclusions of the Winton et al. paper?

    Zoia Ladescu Muresan contributed to this comment.

  6. Everybody can have an opinion about the journal’s harshness in retracting Winton et al., but none of us have access to all the elements of the inquiry that led the journal to such a decision. More importantly, this incident sheds light on the important scientific question of whether there is intraneuronal accumulation of Aβ and whether it is responsible for neuronal toxicity. Many authors detected intracellular accumulation of Aβ and others suggested the contrary. I believe that all of them were confident in their data. Then how do we explain the discrepancies that have led to so much controversial data?

    Our experience in this field exemplifies the traps one can encounter when working in situ with antibodies characterized in vitro, essentially by western blot. We also examined the intracellular label observed early in 3xTg mice. We first used antibodies recognizing the N-terminal of the Aβ sequence, either pan-Aβ antibodies such as 6E10 or 2H3 or cleavage-specific N-terminal antibodies such as FCA18 or 82E1. With these, we observed a strong punctiform staining, which accumulated with age. We first believed that this intraneuronal staining corresponded to Aβ, because it was not detected with anti-APP C-terminal antibodies that normally would be expected to recognize C99 but not Aβ. However, very puzzlingly, we were unable to detect this staining with Aβ C-terminal specific antibodies (Aβ42 or Aβ40), even though we tried several such antibodies.

    Performing ELISA analysis, we were unable to detect Aβ in young mice, in which this punctiform labeling was clearly detected. In order to resolve these paradoxical data, we pursued other ways to discriminate between Aβ and C99. First, we tried a pharmacological approach. When older mice (i.e., in which low Aβ levels could be detected) were treated with a γ-secretase inhibitor, we found a clear reduction in Aβ by ELISA and a strong increase in APP-CTFs by western blot. Because the punctiform labeling detected with a set of distinct antibodies directed against the N-terminal of the Aβ sequence (FCA18, 82E1, 6E10 and 2H3) was strongly enhanced, this labeling could not correspond to Aβ but should be C99.

    We also compared 2xTgAD and 3xTgxAD mice. We found that 2xTgAD mice (bearing APPswe and TauP301L, but expressing WT PS1) displayed much lower Aβ levels by ELISA, but similar C99 levels by western blot. Importantly, the intraneuronal punctiform staining in these mice, whatever their age, was identical between these two types of mice, again strongly suggesting that this labeling should correspond to C99, not Aβ. 

    So why do APP C-terminal antibodies not detect this punctiform immunostaining if, as evidenced by these distinct approaches, the label corresponds to C99? One possibility is that C99 is misfolded or aggregated and therefore cannot be recognized by these antibodies because a linear epitope is masked. This would be in agreement with the fact that pretreatment of the tissue with formic acid is essential to reveal this staining. 

    Our data shows that the delineation of antibody specificity based on biochemical in vitro analysis (western blots, etc.) cannot be taken as definitive and should be cautiously considered before equating label/lack of label to presence/absence of the "antigen" when studying tissues or organs. In the absence of formal identification of in situ antigens, multiple approaches should be envisioned. Overall, the network of approaches and panel of immunological tools together demonstrate that Aβ does not accumulate intraneuronally, at least at early stages in the 3xTgAD mouse, and that C99 is the main contributor to the early intracellular APP-like immunoreactive material in these mice.

  7. As well as fuelling one of the scientific debates in the field, this retraction also should serve as a caution to scientists, reviewers, and editors. It is understandable how easy it is for figures to get accidentally changed in multiple revisions of papers. We all need to be careful in these revisions, and could use the emerging data handling, sharing, and repository tools to help us keep track of the primary data represented in our figures. Although authors are ultimately responsible for the quality of their data and papers, surely peer reviewers and journal editors also bear some responsibility for quality checking publications. Two of the primary values that publishers add to the scientific endeavor is the cultivation of peer review of our work and the editorial decisions about which papers are of high enough quality to publish.

  8. The intraneuronal accumulation of Aβ, APP, and APP fragments, and the significance of these molecules in the evolution of the Alzheimer’s disease (AD) pathology, has been an issue of much debate in recent years. The earliest demonstration of an “Aβ-immunoreactive material” accumulation inside neuronal cell bodies came from in vitro studies and soon from histopathological observations in postmortem human brains from AD and Down’s syndrome sufferers. This has been followed by a large number of similar observations in a variety of mice and rat transgenic models of the AD-like amyloid pathology. These observations as well as opposing views were the object of a review (Cuello et al., 2012). 

    More recently, we addressed this problem experimentally by applying a variety of approaches to assess with a higher degree of certainty the occurrence of intraneuronal Aβ-immunoreactive material in an AD-like transgenic rat (Iulita et al., 2014). For that study we investigated the occurrence of immunoreactive sites for APP/CTF and for Aβ, applying a wide panel of well-characterized monoclonal and polyclonal antibodies in conjugation with high resolution microscopy. This procedure allowed for a remarkable resolution of the sites of origin of fluorescent signals, revealing the presence of intracytoplasmic Aβ-immunoreactivity with an immunological signal localization that was clearly distinct from signals emanating from APP/CTFs sites (Iulita et al., 2014). This publication further reinforced the idea that at least some of the intraneuronal Aβ is likely to exist in oligomeric form, as revealed with the NU1 monoclonal antibody generated by Bill Klein (Klein et al., 2007).

    In the same multi-dimensional study, we demonstrated that it is already possible to detect abundant soluble Aβ40 and Aβ42 peptides with a specific, well-established ELISA protocol at a stage when only intracellular Aβ-immunoreactivity is microscopically detectable. It is highly likely that this intraneuronal Aβ material is already in equilibrium with the extracellular space and perhaps responsible for early pathological effects. Thus, we have shown in the same study that some of the Aβ peptides reach the cerebrospinal fluid and can be identified unequivocally as Aβ38, Aβ39, Aβ40, and Aβ42 by mass spectrometry.

    The pathological relevance of this early intraneuronal Aβ accumulation is highlighted by the fact that at this stage, in the McGill-R-Thy1-APP rat transgenic model, Aβ accumulation is accompanied by a) significant cognitive impairments (Iulita et al., 2014); b) an early, pre-plaque pro-inflammatory process (Hanzel et al., 2014); and c) impairments in in vivo hippocampal LTP formation which were reverted with the application of an anti-Aβ monoclonal antibody (McSA1) (Qi et al., 2014).

    References:

    . Evidence for the accumulation of Abeta immunoreactive material in the human brain and in transgenic animal models. Life Sci. 2012 Jun 13; PubMed.

    . Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun. 2014 Jun 5;2:61. PubMed.

    . Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 2007 Jan;100(1):23-35. PubMed.

    . Neuronal driven pre-plaque inflammation in a transgenic rat model of Alzheimer's disease. Neurobiol Aging. 2014 Oct;35(10):2249-62. Epub 2014 Mar 28 PubMed.

    . Longitudinal testing of hippocampal plasticity reveals the onset and maintenance of endogenous human Aß-induced synaptic dysfunction in individual freely behaving pre-plaque transgenic rats: rapid reversal by anti-Aß agents. Acta Neuropathol Commun. 2014 Dec 24;2:175. PubMed.

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References

Research Models Citations

  1. 3xTg
  2. 5xFAD

Webinar Citations

  1. Intraneuronal Aβ Accumulation—More Evidence, Less Controversy?
  2. Intraneuronal Aβ: Was It APP All Along?

Paper Citations

  1. . Intraneuronal APP, not free Aβ peptides in 3xTg-AD mice: implications for tau versus Aβ-mediated Alzheimer neurodegeneration. J Neurosci. 2011 May 25;31(21):7691-9. PubMed.
  2. . Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
  3. . Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody. Mol Neurodegener. 2012;7:8. PubMed.
  4. . AβPP Accumulation and/or Intraneuronal Amyloid-β Accumulation? The 3xTg-AD Mouse Model Revisited. J Alzheimers Dis. 2012 Jan 1;28(4):897-904. PubMed.
  5. . Intracellular Aβ pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study. Acta Neuropathol Commun. 2014 Jun 5;2:61. PubMed.
  6. . The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci. 2012 Nov 14;32(46):16243-55a. PubMed.
  7. . Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease. Brain. 2015 Jun;138(Pt 6):1722-37. Epub 2015 Mar 1 PubMed.

External Citations

  1. website 
  2. Retraction Watch
  3. DrugMonkey
  4. Philadelphia Inquirer
  5. statement 
  6. letter 
  7. correction or retraction

Further Reading