Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and alzheimer disease-like transgenic mouse models

Jeffrey L. Frost, Kevin X. Le, Holger Cynis, Elizabeth Ekpo, Martin Kleinschmidt, Roberta M. Palmour, Frank R. Ervin, Shikha Snigdha, Carl W. Cotman, Takaomi C. Saido, Robert J. Vassar, Peter St George-Hyslop, Tsuneya Ikezu, Stephan Schilling, Hans Ulrich Demuth, Cynthia A. Lemere

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Amyloid-β (Aβ) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Aβ), are a major species deposited in the brain of Alzheimer disease (AD) patients. Recent studies suggest that this isoform shows higher toxicity and amyloidogenecity when compared to full-length Aβ peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Aβ deposition in humans and animal models. PyroGlu-3 Aβ immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Aβ IR. PyroGlu-3 Aβ is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Aβ deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Aβ deposition preceding pyroGlu-3 Aβ deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Aβ is a major species of β-amyloid deposited early in diffuse and focal plaques and cerebral amyloid angiopathy in humans and nonhuman primates, whereas it is deposited later in a subset of focal and vascular amyloid in AD-like transgenic mouse models. Given the proposed decisive role of pyroGlu-3 Aβ peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.

Original languageEnglish (US)
Pages (from-to)369-381
Number of pages13
JournalAmerican Journal of Pathology
Volume183
Issue number2
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and alzheimer disease-like transgenic mouse models'. Together they form a unique fingerprint.

  • Cite this

    Frost, J. L., Le, K. X., Cynis, H., Ekpo, E., Kleinschmidt, M., Palmour, R. M., Ervin, F. R., Snigdha, S., Cotman, C. W., Saido, T. C., Vassar, R. J., George-Hyslop, P. S., Ikezu, T., Schilling, S., Demuth, H. U., & Lemere, C. A. (2013). Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and alzheimer disease-like transgenic mouse models. American Journal of Pathology, 183(2), 369-381. https://doi.org/10.1016/j.ajpath.2013.05.005