TY - JOUR
T1 - Pyroglutamate-3 amyloid-β deposition in the brains of humans, non-human primates, canines, and alzheimer disease-like transgenic mouse models
AU - Frost, Jeffrey L.
AU - Le, Kevin X.
AU - Cynis, Holger
AU - Ekpo, Elizabeth
AU - Kleinschmidt, Martin
AU - Palmour, Roberta M.
AU - Ervin, Frank R.
AU - Snigdha, Shikha
AU - Cotman, Carl W.
AU - Saido, Takaomi C.
AU - Vassar, Robert J.
AU - George-Hyslop, Peter St
AU - Ikezu, Tsuneya
AU - Schilling, Stephan
AU - Demuth, Hans Ulrich
AU - Lemere, Cynthia A.
N1 - Funding Information:
Funded in part by the NIH/National Institute on Aging grants R01 AG020159 and AG040092 (C.A.L.) and an anonymous foundation (C.A.L.).
PY - 2013/8
Y1 - 2013/8
N2 - 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.
AB - 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.
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U2 - 10.1016/j.ajpath.2013.05.005
DO - 10.1016/j.ajpath.2013.05.005
M3 - Article
C2 - 23747948
AN - SCOPUS:84880632451
SN - 0002-9440
VL - 183
SP - 369
EP - 381
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 2
ER -