title: Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse models.
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.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Frost
authors.forename: Kevin X
authors.initials: KX
authors.lastname: Le
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ekpo
authors.forename: Martin
authors.initials: M
authors.lastname: Kleinschmidt
authors.forename: Roberta M
authors.initials: RM
authors.lastname: Palmour
authors.forename: Frank R
authors.initials: FR
authors.lastname: Ervin
authors.forename: Shikha
authors.initials: S
authors.lastname: Snigdha
authors.forename: Carl W
authors.initials: CW
authors.lastname: Cotman
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Vassar
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Tsuneya
authors.initials: T
authors.lastname: Ikezu
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Lemere
mesh_terms: D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004285:Dogs; D004314:Down Syndrome / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D058225:Plaque, Amyloid / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011761:Pyrrolidonecarboxylic Acid