Could Antibodies Against Pyroglutamate Safely Break Down Plaques?

Most Aβ antibodies in development can prevent plaque buildup, but few eliminate existing plaques. Enter a new monoclonal antibody developed by scientists at Eli Lilly and Company, Indianapolis, Indiana. Dubbed mE8, it seems to target plaques directly by binding the rare pyroglutamate form of Aβ (pGluAβ). As reported in the December 6 Neuron, mE8 bound the modified peptide in amyloid deposits in an AD mouse model, activated microglia to clear them, and did it all without causing microhemorrhages, which has been a problem in AD immunotherapy. Results line up with data published earlier this year by Cynthia Lemere and colleagues at Brigham and Women’s Hospital, Boston, and could have implications for Alzheimer’s treatment.

Developing "therapies that can effectively remove and decrease toxicity of pre-existing plaques and CAA [cerebral amyloid angiopathy] without causing side effects is a major goal," wrote David Holtzman and Jee Hoon Roh of Washington University School of Medicine, St. Louis, Missouri, in an accompanying editorial.

Anti-Aβ antibodies tested in clinical trials bind both soluble and insoluble forms of Aβ, but have not been shown to clear larger deposits. Ronald DeMattos and colleagues at Lilly wanted to raise an antibody that would target and clear plaques directly. For an antigen, the researchers zeroed in on pGluAβ, which is found almost exclusively in amyloid deposits but not in blood or cerebrospinal fluid. The peptide forms when two amino acids are clipped from the N-terminus of Aβ, leaving a glutamate that is enzymatically cyclized. The resulting pGluAβ resists degradation, is extremely hydrophobic, and aggregates quickly.

To create a pGluAβ antibody, the researchers adopted a similar monoclonal strategy to that used by Lemere’s group (see Frost et al., 2012). DeMattos and colleagues immunized mice with pGluAβ and, after cloning B cells, found an antibody—mE8—that recognized only that form of Aβ. Though it bound both soluble and insoluble pGluAβ, the team hypothesized the antibody would be plaque specific, since pGluAβ exists almost entirely in those deposits.

Engineered on an IgG1 backbone, mE8 weakly activated microglia, while on an IgG2a backbone the antibody elicited a stronger microglial response. IgG2 antibodies typically have better effector function, meaning they robustly stimulate immune cells. To test these antibodies in vivo, the scientists intraperitoneally injected aged, plaque-laden PDAPP mice (Johnson-Wood et al., 1997) (23 to 24 months old) weekly with mE8-IgG1, mE8-IgG2a, or 3D6, an antibody that binds to soluble and insoluble Aβ42. 3D6 is the mouse forerunner of the human bapineuzumab antibody (see ARF related news story).

After three months, animals treated with mE8-IgG1 and mE8-IgG2a contained 38 and 53 percent less Aβ, respectively, than controls. The difference between the two IgG versions suggests that stronger microglial activation translates to greater Aβ clearance. “This confirms that microglia are likely one of the key players in plaque clearance,” DeMattos told Alzforum. These mice showed no signs of microhemorrhage, which has plagued development of anti-Aβ immunotherapy in humans (see ARF related news story and ARF news story).

While the mE8 antibody helped clear plaques, it did not prevent their formation as effectively. Though young mice (5.5-months-old) treated with mE8-IgG2a for seven months accumulated 30 percent less plaque relative to controls, the difference was not significant. In contrast, mice treated with 3D6 made 70 percent less plaque during the same period. The mE8 antibody may not have worked as well in younger animals because of a dearth of pGluAβ early in disease, the authors wrote. However, Lemere found that mAb07/1 lowered plaque burden in both treatment and prevention paradigms. She is unsure why mAb07/1 and mE8 would differ in this respect. “We believe one of the reasons we see prevention is because pGluAβ can act as a seed for general Aβ deposition,” she told Alzforum. Altogether, DeMattos’ results suggest that antibodies that bind soluble Aβ help prevent plaque deposition, while those that mostly bind plaques, such as mE8, primarily clear existing amyloid.

What mechanism underlies the difference between antibody types? DeMattos suggested that antibodies that bind soluble Aβ, such as 3D6, do not clear plaques well because they become mired in the halo of free Aβ surrounding them. Saturated with these smaller Aβ species, the antibodies never reach the plaques. However, since mE8 specifically binds pGluAβ, it slips past the cloud of Aβ and goes directly to the plaques. That may also explain why mE8 does not cause microhemorrhages. DeMattos and colleagues claim that mE8 is trapped by plaques until cleared by microglia. Antibodies that do not bind plaques, on the other hand, are free to diffuse to the vasculature where they release their Aβ cargo, which then builds up along vessels, causing microbleeds (see Winkler et al., 2001). “It suggests that you can clear existing plaques by phagocytosis and not have this [microhemorrhage] liability,” said DeMattos.

How can an antibody that recognizes such an uncommon Aβ peptide induce such substantial plaque reduction? Lemere suggested in her paper that once pGluAβ antibodies bind plaques, they activate microglia, which then clear Aβ indiscriminately. "That's quite an interesting concept," agreed Dennis Selkoe, Brigham and Women’s Hospital. "It suggests that activating microglia via just a subset of Aβ peptides allows a more generalized phagocytic clearing of plaque amyloid."

Does this ultimately help the mice? “This study lacks any information about beneficial effects, such as rescue of synaptotoxicity, neurotoxicity, or behavioral deficits,” said Thomas Bayer, University of Göttingen, Germany. He previously reported that a pGluAβ antibody specific for non-plaque oligomers reduced plaque deposition and alleviated anxiety in an AD mouse model (see Wirths et al., 2010). He believes that pGluAβ oligomers, while absent from CSF and blood, exist between or within neurons, where they exert their toxicity—thus representing the ideal target. Lemere’s group plans to present behavioral, pathological, and biochemical characterization of their pGluAβ antibody this coming March at the AD/PD meeting in Florence, Italy.

DeMattos’ results may have implications for human AD treatment, speculated some. For example, recent results on solanezumab—Eli Lilly's humanized monoclonal antibody that binds soluble Aβ—indicate a modest cognitive benefit and trend toward reduced amyloid burden in a mild AD patient subgroup (see ARF related news story). “This paper leads me to suggest combining solanezumab with a humanized form of a plaque-directed antibody like mE8,” said Selkoe. “The two antibodies might complement one another, with solanezumab targeting soluble monomers and an mE8-like antibody targeting fibrillar plaques.”

The mE8 antibody is not suitable for human use in its murine form, but Lilly has humanized it and plans to begin a Phase 1 clinical trial by 2014, a Lilly representative told Alzforum via e-mail. Whether pGluAβ antibodies will behave the same way in humans as they do in mice is unclear, however. Some evidence suggests much more pGluAβ exists in the AD brain than in transgenic mouse models (see ARF related news story), though DeMattos says his data consistently indicate similar levels in AD brain as in the PDAPP mice. If pGluAβ was more prominent, it might make up more of the peri-plaque halo of Aβ and contribute to microhemorrhage. “A real test of this concern would be to administer chronic passive immunization against pGluAβ in a mouse that overexpresses and deposits it,” said Lemere.—Gwyneth Dickey Zakaib

Comments

  1. 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. 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. PubMed.

    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. Pyroglutamate Abeta pathology in APP/PS1KI mice, sporadic and familial Alzheimer's disease cases. J Neural Transm. 2010 Jan;117(1):85-96. PubMed.

    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 A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem. 2010 Dec 31;285(53):41517-24. PubMed.

    View all comments by Thomas Bayer

  2. 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., 2012; 2012; Valenti et al., 2013), 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: Lemere C. personal communication (2012).

    References:

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    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. PubMed.

    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. PubMed.

    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. PubMed.

    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. PubMed.

    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. PubMed.

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    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. PubMed.

    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. PubMed.

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    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. Program No. 545.17/F19. 2012 Neuroscience Meeting Planner. New Orleans, LA: Society for Neuroscience, 2012. Online.

    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. PubMed.

    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. PubMed.

    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. PubMed.

    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. PubMed.

    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. PubMed.

    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. PubMed.

    View all comments by Stephan Schilling

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References

News Citations

  1. Washington: Recap of Drug Discovery for Neurodegeneration Meeting, Part 1
  2. Chicago: Bapineuzumab’s Phase 2—Was the Data Better Than the Spin?
  3. Paris: Renamed ARIA, Vasogenic Edema Common to Anti-Amyloid Therapy
  4. CTAD: New Data on Sola, Bapi, Spark Theragnostics Debate
  5. Salzburg: Aβ’s N-terminal Shenanigans

Therapeutics Citations

  1. Solanezumab

Paper Citations

  1. 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. PubMed.
  2. Johnson-Wood K, Lee M, Motter R, Hu K, Gordon G, Barbour R, Khan K, Gordon M, Tan H, Games D, Lieberburg I, Schenk D, Seubert P, McConlogue L. Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1550-5. PubMed.
  3. Winkler DT, Bondolfi L, Herzig MC, Jann L, Calhoun ME, Wiederhold KH, Tolnay M, Staufenbiel M, Jucker M. Spontaneous hemorrhagic stroke in a mouse model of cerebral amyloid angiopathy. J Neurosci. 2001 Mar 1;21(5):1619-27. PubMed.
  4. 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 A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem. 2010 Dec 31;285(53):41517-24. PubMed.

Further Reading

Papers

  1. 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. PubMed.
  2. 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. PubMed.
  3. 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. PubMed.
  4. Scheltens P, Goos JD. Dementia in 2011: Microbleeds in dementia--singing a different ARIA. Nat Rev Neurol. 2012 Feb;8(2):68-70. PubMed.
  5. 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 A{beta} oligomers in Alzheimer disease: a novel tool for therapy and diagnosis. J Biol Chem. 2010 Dec 31;285(53):41517-24. PubMed.
  6. 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. PubMed.

Primary Papers

  1. Roh JH, Holtzman DM. Stealth attack: plaque-specific antibody allows for efficient Aβ removal without side effects. Neuron. 2012 Dec 6;76(5):859-61. PubMed.
  2. 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. PubMed.

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