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Article type: Research Article
Authors: Mandler, Markusa | Rockenstein, Edwardb | Ubhi, Kirenb | Hansen, Lawrenceb; c | Adame, Anthonyb | Michael, Sarahb | Galasko, Douglasb | Santic, Radmilaa | Mattner, Franka; * | Masliah, Eliezerb; c; *
Affiliations: [a] AFFiRiS AG, Vienna Biocenter, Vienna, Austria | [b] Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA | [c] Department of Pathology, University of California, San Diego, La Jolla, CA, USA
Correspondence: [*] Correspondence to: Dr. Eliezer Masliah, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093-0624, USA. Tel.: +1 858 534 8992; Fax: +1 858 534 6232; E-mail: emasliah@ucsd.edu and Dr. Frank Mattner, AFFiRiS AG, Vienna Biocenter, 1030 Vienna, Austria. Tel.: +43 (1) 7981575 300; Fax: +43 (1) 7981575 311; E-mail: Frank.Mattner@affiris.com.
Abstract: The neurodegenerative pathology in patients with Alzheimer's disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-β (Aβ) species. Among them, recent studies indicate that the pyroglutamate modification of Aβ (pE(3)Aβ) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aβ aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aβ across the spectrum of AD and in the brains of amyloid-β protein precursor (AβPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated D129) that specifically recognizes pE(3)Aβ and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AβPP tg mice. We found that in early stages of AD and young AβPP tg mice pE(3)Aβ was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AβPP tg mice, pE(3)Aβ was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aβ might contribute to early cognitive dysfunction in AD.
Keywords: ELISA, monoclonal antibody, mThy1-hAβPP tg, synapse, Tg2576
DOI: 10.3233/JAD-2011-111208
Journal: Journal of Alzheimer's Disease, vol. 28, no. 4, pp. 783-794, 2012
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