The authors convincingly show that they have generated a specific antibody to one of the most AD-associated Aβ isoforms both with regard to neuropathology and cognitive deficits. They present data on the diagnostic and therapeutic potential of the antibody. I would love to see if the antibody could be used to monitor the possible acute emergence of AβpE3 peptides in CSF in response to successful passive or active anti-Aβ immunization.

View all comments by Henrik Zetterberg

The Therapeutic and Diagnostic Potential of Anti AβpE3 Strategies
The article by the team led by Wirths and Bayer is a further step forward in clarifying the role of an abundant and apparently very toxic Aβ species in human brain deposits: N-pyroglutamyl Aβ (Wirths et al., 2010).

Especially oligomeric forms of Aβ were described as neurotoxic; however, the toxicity of Aβ peptides is still a matter of debate, since most of the generated APP-overexpressing mouse models show profound plaque deposition surprisingly in combination with a lack of neuron loss or robust cognitive impairment. Obviously, a crucial step or agent for the development of the disease must be underrepresented or lacking in most of the model systems (compare Maeda et al., 2007).

In contrast to the Aβ extracted from brains of AD mouse models, the majority of Aβ peptides deposited in human brain are N-terminally processed. Besides isomerization and racemization at positions 1 and 7 of the Aβ sequence, a substantial amount of Aβ peptides are N-terminally truncated and modified by a pyroglutamyl...  Read more

The Therapeutic and Diagnostic Potential of Anti AβpE3 Strategies
The article by the team led by Wirths and Bayer is a further step forward in clarifying the role of an abundant and apparently very toxic Aβ species in human brain deposits: N-pyroglutamyl Aβ (Wirths et al., 2010).

Especially oligomeric forms of Aβ were described as neurotoxic; however, the toxicity of Aβ peptides is still a matter of debate, since most of the generated APP-overexpressing mouse models show profound plaque deposition surprisingly in combination with a lack of neuron loss or robust cognitive impairment. Obviously, a crucial step or agent for the development of the disease must be underrepresented or lacking in most of the model systems (compare Maeda et al., 2007).

In contrast to the Aβ extracted from brains of AD mouse models, the majority of Aβ peptides deposited in human brain are N-terminally processed. Besides isomerization and racemization at positions 1 and 7 of the Aβ sequence, a substantial amount of Aβ peptides are N-terminally truncated and modified by a pyroglutamyl (pE) residue (Roher et al., 1993).

The modification renders Aβ peptides more hydrophobic due to the loss of N-terminal charges, and AβpE3 shows a substantially enhanced aggregation propensity compared to Aβ1-40/42. In addition, AβpE3 is more toxic to primary neuronal and glial cell cultures than Aβ1-42, and the pyroglutamated forms of Aβ have been shown to be poorly degraded by cultured astrocytes (Russo et al., 2002; Schilling et al., 2006).

Therefore, the formation of AβpE3 leads to further stabilization of a per se amyloidogenic peptide. Giving constant anabolic and catabolic processes leading to generation and clearance of Aβ peptides throughout life, the presence of such highly toxic and amyloidogenic Aβ species could represent a starting point for disease initiation (Gunn et al., 2010).

Since the discovery that AβpE3 and AβpE11 formation is catalyzed by the QCs (glutaminyl cyclases; see Schilling et al., 2004 and Cynis et al., 2006), four major routes of dealing with these peptide species are possible:

• Inhibition of QC with orally available small molecule inhibitors
• Passive vaccination against AβpE
• Active vaccination using AβpE peptides or epitope-mimicking peptides
• Vaccination against AβE3, the precursor molecules of AβpE3

All these pathways are explored intensively (Schilling et al., 2008 and Gardberg et al., 2009), and some have now reached preclinical stage.

While vaccination is perhaps primarily targeting extracellular AβpE3, QC-inhibition can take place within the cell. pE-formation by QC occurs preferentially at acid pH-values, as they are found in the Golgi and/or within secretory vesicles (Cynis et al., 2006; Hartlage-Rübsamen et al., 2009). Where these peptides—intraneuronal or interstitial—unfold most of their toxicity remains to be seen. However, generating minute amounts of AβpE3 by directing an appropriate construct into the secretory apparatus of mice brains reveals extraordinary intraneuronal toxicity, neuron loss, and massive gliosis (Wirths et al., 2009). The neuron loss and glial stimulation dramatically exceeds that usually observed with hAPP-transgenic mouse models, which primarily produce full-length Aβ.

That AβpE3 generates—similar as pGlu-ABri or pGlu-ADan—rapidly degradation-resistant oligomers has been previously shown (Schlenzig et al., 2009). The extraordinary cytotoxicity of AβpE3 containing oligomers was demonstrated during the hot topic poster session of the 2010 ICAD meeting in Honolulu (Demuth et al., 2010), and further progress studying the tau-dependent mechanism was presented at SfN 2010 by Justin Nussbaum. That the new antibody 9D5 is capable to discriminate AD patients from non-demented age-matched controls is one of the major achievements described in the new paper by Wirths et al. (2010).

Also, the reduction of AβpE3 by passive immunization of tg mice is a striking result corroborated by the findings achieved by QC-inhibition (Schilling et al., 2008; Demuth et al., 2010), and which is paralleling the effective passive vaccination applying an AβpE3-specific monoclonal antibody raised against a monomeric epitope structure reported at the SFN 2010 Meeting by Jeff Frost and colleagues.

Considering the multiple structural forms misfolding peptides can adopt, it might be conceivable that antibodies raised against differently presented or synthesized epitopes recognize different monomeric or oligomeric species with different sensitivity and specificity. Using the monomer-specific antibody for immunohistochemistry in different laboratories, clear intraneuronal AβpE3 immunoreactivity partly colocalized with QC in mouse and human brain can be observed (Roßner et al.).

Intriguingly, while we did not find detectable amounts of AβpE3 in human plasma using our AβpE mAb, the AβpE3 oligomer-specific monoclonal antibody 9D5 recognizes the peptide in plasma of normal and healthy controls. Wirths et al. report in their paper a significant reduction by 46 percent as compared to healthy controls. If this result is supported by material and data of much greater patient populations, the antibody 9D5 may become a new breakthrough in AD-diagnostics and also may be an important new immunotherapy reagent.

References:
Wirths O, Erck C, Martens H, Harmeier A, Geumann C, Jawhar S, Kumar S, Multhaup G, Walter J, Ingelsson M, Degerman-Gunnarsson M, Kalimo H, Huitinga I, Lannfelt L, Bayer TA. Identification of low molecular weight pyroglutamate Abeta oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem. 2010 Oct 22. Abstract

Maeda J, Ji B, Irie T, Tomiyama T, Maruyama M, Okauchi T, Staufenbiel M, Iwata N, Ono M, Saido TC, Suzuki K, Mori H, Higuchi M, Suhara T. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography. J Neurosci. 2007 Oct 10;27(41):10957-68. Abstract

Roher AE, Palmer KC, Yurewicz EC, Ball MJ, Greenberg BD. Morphological and biochemical analyses of amyloid plaque core proteins purified from Alzheimer disease brain tissue. J Neurochem. 1993 Nov;61(5):1916-26. Abstract

Russo C, Violani E, Salis S, Venezia V, Dolcini V, Damonte G, Benatti U, D'Arrigo C, Patrone E, Carlo P, Schettini G. Pyroglutamate-modified amyloid beta-peptides--AbetaN3(pE)--strongly affect cultured neuron and astrocyte survival. J Neurochem. 2002 Sep;82(6):1480-9. Abstract

Schilling S, Lauber T, Schaupp M, Manhart S, Scheel E, Böhm G, Demuth HU. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry. 2006 Oct 17;45(41):12393-9. Abstract

Gunn AP, Masters CL, Cherny RA . Pyroglutamate-Abeta: Role in the natural history of Alzheimer's disease. Int J Biochem Cell Biol. 2010 Sep 15. Abstract

Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004 Apr 9; 563(1-3):191-6. Abstract

Cynis H, Rahfeld JU, Stephan A, Kehlen A, Koch B, Wermann M, Demuth HU, Schilling S. Isolation of an isoenzyme of human glutaminyl cyclase: retention in the Golgi complex suggests involvement in the protein maturation machinery. J Mol Biol. 2008 Jun 20;379(5):966-80. Abstract

Gardberg A, Dice L, Pridgen K, Ko J, Patterson P, Ou S, Wetzel R, Dealwis C. Structures of Abeta-related peptide--monoclonal antibody complexes. Biochemistry. 2009 Jun 16;48(23):5210-7. Abstract

Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA. Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009 Oct;118(4):487-96. Abstract

Schlenzig D, Manhart S, Cinar Y, Kleinschmidt M, Hause G, Willbold D, Funke SA, Schilling S, Demuth HU. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry. 2009 Jul 28;48(29):7072-8. Abstract

Hartlage-Rübsamen M, Staffa K, Waniek A, Wermann M, Hoffmann T, Cynis H, Schilling S, Demuth HU, Rossner S. Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain. Int J Dev Neurosci. 2009 Dec;27(8):825-35. Abstract

Demuth HU, Bloom GS, Lemere CA. Pyroglutamated β-amyloid Is Toxic, Highly Abundant in Alzheimer's Brain, Amplifies Tau-dependent Beta-amyloid Cytotoxicity and can be Attenuated by Passive Immunization Or Inhibition Of Glutaminyl Cyclase. ICAD 2010, Hot Topic Poster: Control/Tracking Number: 10-HT-3507-ALZ.

Nussbaum J, Cynis H, Schilling S, Demuth HU, Bloom GS. Pyroglutamate-modified β-amyloid amplifies tau-dependent cytotoxicity of conventional β-amyloid. Program#/Poster#: 321.13, Monday, Nov 15, 2010, 11:00 AM -11:15 AM.

Frost JL, Liu B, Shi Q, Kleinschmidt M, Demuth HU, Schilling S, Lemere CA. Passive and active pyroglutamate-3 Aβ (AβN3pE) immunotherapy in AD-like transgenic mouse models. Program#/Poster#: 650.6/H38, Tuesday, Nov 16, 2010, 2:00 PM—3:00 PM.

Morawski M, Hartlage-Rubsamen M, Jager C, Waniek A, Schilling S, Schwab C, McGeer PL, Arendt T, Demuth HU, Rossner S. Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease. Acta Neuropathol 2010 120(2), 195-207. Abstract

Rossner S, Hartlage-Ruebsamen, M, Schilling, S, Demuth HU. Glutaminyl Cyclase as Novel pharmacological target for AD therapy. P13 Clinical Trials on Alzheimer’s Disease, Toulouse, 4th Nov. 2010.

View all comments by Hans-Ulrich Demuth

Passive immunization is one of the central themes for AD therapy. The question is, What is the appropriate target? The paper by DeMattos and colleagues argues that using mE8-IgG2a, a monoclonal antibody (mAb) specific for the pyroglutamate Aβ (pGluAβ) found in plaques is a new tool for therapy. The main message is that the pGluAβ mAb reduces deposited amyloid without inducing microhemorrhage.

When we look at the history behind Aβ immunotherapy, we see that first the AD field believed that plaques are toxic and their removal beneficial for the patients. That turned out to be false and produced significant side effects like hemorrhages. Next, the field turned to soluble oligomers of different size, suggesting that they should be targeted. There is convincing evidence for that notion, in my view. Especially, N-truncated forms of Aβ starting with pyroglutamate proved to be one of the seeding oligomers.

Already in 2010, we generated a monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of pGluAβ and studied their potential involvement in disease....  Read more

Passive immunization is one of the central themes for AD therapy. The question is, What is the appropriate target? The paper by DeMattos and colleagues argues that using mE8-IgG2a, a monoclonal antibody (mAb) specific for the pyroglutamate Aβ (pGluAβ) found in plaques is a new tool for therapy. The main message is that the pGluAβ mAb reduces deposited amyloid without inducing microhemorrhage.

When we look at the history behind Aβ immunotherapy, we see that first the AD field believed that plaques are toxic and their removal beneficial for the patients. That turned out to be false and produced significant side effects like hemorrhages. Next, the field turned to soluble oligomers of different size, suggesting that they should be targeted. There is convincing evidence for that notion, in my view. Especially, N-truncated forms of Aβ starting with pyroglutamate proved to be one of the seeding oligomers.

Already in 2010, we generated a monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of pGluAβ and studied their potential involvement in disease. Passive immunization of 5xFAD mice with 9D5 significantly reduced overall Aβ plaque load and pGluAβ levels, and normalized behavioral deficits. These data indicated that 9D5 is a therapeutically effective monoclonal antibody targeting low-molecular-weight pGluAβ oligomers. These oligomers are likely to affect other Aβ species and act as seed for oligomerization in vivo (Wirths et al., 2010b). 9D5 does not react at all with monomers or dimers, and plaques are only very rarely detected with this antibody. This is in contrast to pGluAβ antibodies 2-48 and 1-57 we have previously made that react with all forms and, of course, detect all plaques in sporadic and familial AD and two mouse models (Wirths et al., 2010a).

Cindy Lemere has demonstrated that passive immunization of APPswe/PS1ΔE9 transgenic mice with a highly specific monoclonal antibody against pGluAβ significantly reduced total plaque deposition and appeared to lower gliosis in the hippocampus and cerebellum in both prevention and therapeutic studies. Insoluble Aβ levels in brain homogenates were not significantly different between immunized and control mice. Microhemorrhage was not observed with anti-pyroglutamate-Aβ immunotherapy (Frost et al., 2012).

Now we learn that plaques are again an interesting target, this time with an antibody that recognizes all forms of pGluAβ aggregated in plaques. No side effects, such as hemorrhages, were observed after passive immunization.

This work published by Ronald DeMattos and colleagues is interesting, but leaves the field with many questions unanswered. Mostly neuropathological and biochemical data were presented. The most important experiment, i.e., whether the treatment is beneficial for the mice or not, has not yet been done. Does the pGluAβ antibody rescue, or at least normalize, behavioral deficits as 9D5 did? What effects can be seen on synaptic deficits and neuron loss?

Such questions could be addressed using different available pGluAβ antibodies and studying their therapeutic potential in mouse models for AD. Our oligomer-specific antibody 9D5 is commercially available at Synaptic Systems, Goettingen, Germany.

References:
Frost JL, Liu B, Kleinschmidt M, Schilling S, Demuth HU, Lemere CA (2012) Passive immunization against pyroglutamate-3 amyloid-β reduces plaque burden in Alzheimer-like transgenic mice: a pilot study. Neurodegener Dis 10: 265-270. Abstract

Wirths O, Bethge T, Marcello A, Harmeier A, Jawhar S, Lucassen PJ, Multhaup G, Brody DL, Esparza T, Ingelsson M, Kalimo H, Lannfelt L, Bayer TA (2010a) Pyroglutamate Aβ pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases. J Neural Transm 117: 85-96. Abstract

Wirths O, Erck C, Martens H, Harmeier A, Geumann C, Jawhar S, Kumar S, Multhaup G, Walter J, Ingelsson M, Degerman-Gunnarsson M, Kalimo H, Huitinga I, Lannfelt L, Bayer TA (2010b) Identification of low molecular weight pyroglutamate Aβ oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem 285: 41517-41524. Abstract

View all comments by Thomas Bayer

This paper places an underestimated Aβ species center stage: the pyroglutamated Aβ (pEAβ).

In general, there are several possible approaches to reduce pEAβ species:

1. Preventing such modification by using small molecule inhibitors of glutaminyl cyclase (QC), the enzyme responsible for the modification (Schilling et al., 2004).

2. Clearing such already modified or continuously forming species by active or passive immunization.

According to the mechanism presented in this study, the pEAβ species are seen simply as plaque-specific docking points for immunotherapy and as such being indeed very effective. Work from other groups and ours suggests, however, that these pEAβ species play an important role in the genesis of pathology by way of their significant toxic and seeding potential (Wirths et al., 2009; Morawski et al., 2010; Hartlage-Rübsamen et al., 2011, Alexandru et al., 2011). This view is not represented in the discussion, nor have the available data been adequately acknowledged in the present study.

Moreover, we would like to point out that these pEAβ...  Read more

This paper places an underestimated Aβ species center stage: the pyroglutamated Aβ (pEAβ).

In general, there are several possible approaches to reduce pEAβ species:

1. Preventing such modification by using small molecule inhibitors of glutaminyl cyclase (QC), the enzyme responsible for the modification (Schilling et al., 2004).

2. Clearing such already modified or continuously forming species by active or passive immunization.

According to the mechanism presented in this study, the pEAβ species are seen simply as plaque-specific docking points for immunotherapy and as such being indeed very effective. Work from other groups and ours suggests, however, that these pEAβ species play an important role in the genesis of pathology by way of their significant toxic and seeding potential (Wirths et al., 2009; Morawski et al., 2010; Hartlage-Rübsamen et al., 2011, Alexandru et al., 2011). This view is not represented in the discussion, nor have the available data been adequately acknowledged in the present study.

Moreover, we would like to point out that these pEAβ species cannot simply occur spontaneously. The half-life of the spontaneous oxoproline ring formation means that this process would, under physiological conditions, take years to decades (Seifert et al., 2009; Jawhar et al., 2011). Glutaminyl cyclase activity is required to generate these species readily in living beings, and this enzyme is upregulated early in AD (Schilling et al., 2008, Jawhar et al., 2011; De Kimpe et al., 2012a; De Kimpe et al., 2012b, Valenti et al., 2012), driving or driven also by inflammatory processes (Cynis et al., 2011).

Many studies have clearly shown that in human brain, abundant pE modification of Aβ speeds up aggregation of the peptide. This correlates with its occurrence in deposits, which are detectable by β amyloid-directed PET labels (Maeda et al., 2007), and with its accumulation with disease progression (Pivtoraiko et al., 2012). In contrast, pEAβ is rarely present in CSF and plasma. Moreover, several experiments indicate that diffusible ligands are formed from pEAβ in vitro (Schlenzig et al., 2012) and can be extracted from AD tissue (Piccini et al., 2005, Nussbaum et al., 2012). Diffusible oligomers containing pEAβ forms potently interfere with LTP and neuron viability, as has been recently demonstrated (Nussbaum et al., 2012).

The major driver of these characteristics is the increased surface hydrophobicity of these species—a feature that has also been linked to the toxicity of other amyloid peptides (Schlenzig et al., 2012). In that regard, the study by DeMattos at al. leaves open an important point. Are such oligomers recognized by the antibody, and does this result in functional improvement? Answering this question would strengthen the paper’s conclusions significantly.

The present study concludes that pEAβ does not serve as a species that provokes buildup of deposits. We would respectfully submit that this conclusion is inadequately supported by experimental evidence in this study. The preventive trial with the mE8 antibodies was stopped at an age when PDAPP mice were previously described just to start the deposition; hence, it was not possible to measure how the antibody would have affected further amyloid buildup in the months to come. In addition, the data presented on total Aβ in the prevention and in the therapeutic studies using the mE8 antibodies are difficult to interpret, since the extraction method used does not allow a differentiation between deposited and soluble material at the younger and the older ages of the treated PDAPP mice.

In contrast, preventive passive immunization of APP/PS1 mice has been shown to reduce early plaque load significantly (Frost et al., 2012). This result is further supported by novel double transgenic mouse lines (FAD42 and 5xFAD/hQC; Jawhar et al., 2011; Wittnam et al., 2012) that exhibit early pathology and memory impairment caused by QC-induced pEAβ formation. Also, our own studies applying QC inhibitors in a preventive manner ameliorated general Aβ pathology and behavior impairment late, but also early, during the progression of Aβ formation, aggregation, and deposition (Schilling et al., 2008). Our lead QC inhibitor has nearly completed Phase 1 studies in Europe with excellent data on safety, tolerability, and target engagement.

Finally, contrasting our data with mE8, our pEAβ-specific monoclonal antibody shows plaque lowering, and this reduction appears to correlate with an improvement in behavior also early on (Lemere et al., personal communication). Our antibody specifically recognizes monomeric, oligomeric, fibrillar pEAβ, and mixed Aβ material in vitro. Accordingly, the antibody reduced Aβ in monotherapeutic prophylactic and therapeutic preclinical trials (Frost et al., 2012).

In conclusion, the presented study indeed offers novel and welcome perspectives for the field of immunotherapy. The data published to date remain, however, inconclusive with regard to pEAβ’s role in toxicity.

References:
Demattos RB, Lu J, Tang Y, Racke MM, DeLong CA, Tzaferis JA, Hole JT, Forster BM, McDonnell PC, Liu F, Kinley RD, Jordan WH, Hutton ML. A Plaque-Specific Antibody Clears Existing β-amyloid Plaques in Alzheimer's Disease Mice. Neuron. 2012 Dec 6;76(5):908-20. Abstract

Schilling S, Hoffmann T, Manhart S, Hoffmann M, Demuth HU. Glutaminyl cyclases unfold glutamyl cyclase activity under mild acid conditions. FEBS Lett. 2004 Apr 9;563(1-3):191-6. Abstract

Wirths O, Breyhan H, Cynis H, Schilling S, Demuth HU, Bayer TA. Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 2009 Oct;118(4):487-96. Abstract

Morawski M, Hartlage-Rübsamen M, Jäger C, Waniek A, Schilling S, Schwab C, McGeer PL, Arendt T, Demuth HU, Rossner S. Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease. Acta Neuropathol. 2010 Aug;120(2):195-207. Abstract

Hartlage-Rübsamen M, Staffa K, Waniek A, Wermann M, Hoffmann T, Cynis H, Schilling S, Demuth HU, Rossner S. Developmental expression and subcellular localization of glutaminyl cyclase in mouse brain. Int J Dev Neurosci. 2009 Dec;27(8):825-35. Abstract

Hartlage-Rübsamen M, Morawski M, Waniek A, Jäger C, Zeitschel U, Koch B, Cynis H, Schilling S, Schliebs R, Demuth HU, Rossner S. Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 2011 Jun;121(6):705-19. Abstract

Alexandru A, Jagla W, Graubner S, Becker A, Bäuscher C, Kohlmann S, Sedlmeier R, Raber KA, Cynis H, Rönicke R, Reymann KG, Petrasch-Parwez E, Hartlage-Rübsamen M, Waniek A, Rossner S, Schilling S, Osmand AP, Demuth HU, von Hörsten S. Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate-Aβ formation. J Neurosci. 2011 Sep 7;31(36):12790-801. Abstract

Seifert F, Schulz K, Koch B, Manhart S, Demuth HU, Schilling S. Glutaminyl cyclases display significant catalytic proficiency for glutamyl substrates. Biochemistry. 2009 Dec 22;48(50):11831-3. Abstract

Jawhar S, Wirths O, Schilling S, Graubner S, Demuth HU, Bayer TA. Overexpression of glutaminyl cyclase, the enzyme responsible for pyroglutamate A{beta} formation, induces behavioral deficits, and glutaminyl cyclase knock-out rescues the behavioral phenotype in 5XFAD mice. J Biol Chem. 2011 Feb 11;286(6):4454-60. Abstract

Schilling S, Zeitschel U, Hoffmann T, Heiser U, Francke M, Kehlen A, Holzer M, Hutter-Paier B, Prokesch M, Windisch M, Jagla W, Schlenzig D, Lindner C, Rudolph T, Reuter G, Cynis H, Montag D, Demuth HU, Rossner S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nat Med. 2008 Oct;14(10):1106-11. Abstract

De Kimpe L, Bennis A, Zwart R, van Haastert ES, Hoozemans JJ, Scheper W. Disturbed Ca2+ homeostasis increases glutaminyl cyclase expression; connecting two early pathogenic events in Alzheimer's disease in vitro. PLoS One. 2012;7(9):e44674. Abstract

De Kimpe L, van Haastert ES, Kaminari A, Zwart R, Rutjes H, Hoozemans JJ, Scheper W. Intracellular accumulation of aggregated pyroglutamate amyloid beta: convergence of aging and Aβ pathology at the lysosome. Age (Dordr). 2012 Apr 4. Abstract

Valenti MT, Bolognin S, Zanatta C, Donatelli L, Innamorati G, Pampanin M, Zanusso G, Zatta P, Carbonare LD. Increased Glutaminyl Cyclase Expression in Peripheral Blood of Alzheimer's Disease Patients. J Alzheimers Dis. 2012 Dec 3. Abstract

Cynis H, Hoffmann T, Friedrich D, Kehlen A, Gans K, Kleinschmidt M, Rahfeld JU, Wolf R, Wermann M, Stephan A, Haegele M, Sedlmeier R, Graubner S, Jagla W, Müller A, Eichentopf R, Heiser U, Seifert F, Quax PH, de Vries MR, Hesse I, Trautwein D, Wollert U, Berg S, Freyse EJ, Schilling S, Demuth HU. The isoenzyme of glutaminyl cyclase is an important regulator of monocyte infiltration under inflammatory conditions. EMBO Mol Med. 2011 Sep;3(9):545-58. Abstract

Maeda J, Ji B, Irie T, Tomiyama T, Maruyama M, Okauchi T, Staufenbiel M, Iwata N, Ono M, Saido TC, Suzuki K, Mori H, Higuchi M, Suhara T. Longitudinal, quantitative assessment of amyloid, neuroinflammation, and anti-amyloid treatment in a living mouse model of Alzheimer's disease enabled by positron emission tomography. J Neurosci. 2007 Oct 10;27(41):10957-68. Abstract

Pivtoraiko VN, Abrahamson EE, Debnath ML, Paljug WR, Klunk WE, Mathis CA, Mufson EJ, Dekosky ST, Ikonomovic MD. Increased posterior cingulate pyroglutamate Abeta 42 levels correlate with impaired cognition and increased [H-3]PiB binding in mild cognitive impairment and mild/moderate Alzheimer’s disease. Society for Neuroscience Meeting 2012, New Orleans, Abstract, Program#/Poster#: 545.17/F19.

Schlenzig D, Rönicke R, Cynis H, Ludwig HH, Scheel E, Reymann K, Saido T, Hause G, Schilling S, Demuth HU. N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation. J Neurochem. 2012 Jun;121(5):774-84. Abstract

Piccini A, Russo C, Gliozzi A, Relini A, Vitali A, Borghi R, Giliberto L, Armirotti A, D'Arrigo C, Bachi A, Cattaneo A, Canale C, Torrassa S, Saido TC, Markesbery W, Gambetti P, Tabaton M. beta-amyloid is different in normal aging and in Alzheimer disease. J Biol Chem. 2005 Oct 7;280(40):34186-92. Abstract

Nussbaum JM, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Rönicke R, Reymann K, Hutter-Paier B, Alexandru A, Jagla W, Graubner S, Glabe CG, Demuth HU, Bloom GS. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature. 2012 May 31;485(7400):651-5. Abstract

Piccini A, Zanusso G, Borghi R, Noviello C, Monaco S, Russo R, Damonte G, Armirotti A, Gelati M, Giordano R, Zambenedetti P, Russo C, Ghetti B, Tabaton M. Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch Neurol. 2007 May;64(5):738-45. Abstract

Frost JL, Liu B, Kleinschmidt M, Schilling S, Demuth HU, Lemere CA. Passive immunization against pyroglutamate-3 amyloid-β reduces plaque burden in Alzheimer-like transgenic mice: a pilot study. Neurodegener Dis. 2012;10(1-4):265-70. Abstract

Wittnam JL, Portelius E, Zetterberg H, Gustavsson MK, Schilling S, Koch B, Demuth HU, Blennow K, Wirths O, Bayer TA. Pyroglutamate amyloid β (Aβ) aggravates behavioral deficits in transgenic amyloid mouse model for Alzheimer disease. J Biol Chem. 2012 Mar 9;287(11):8154-62. Abstract

Lemere C. personal communication (2012).

View all comments by Hans-Ulrich Demuth
View all comments by Stephan Schilling