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

Frost, Jeffrey L.Jeffrey L.FrostLe, Kevin X.Kevin X.LeCynis, H.H.CynisEkpo, ElisabethElisabethEkpoKleinschmidt, MartinMartinKleinschmidtPalmour, Roberta M.Roberta M.PalmourErvin, Frank R.Frank R.ErvinSnigdha, ShikhaShikhaSnigdhaCotman, Carl W.Carl W.CotmanSaido, Takaomi C.Takaomi C.SaidoVassar, Robert J.Robert J.VassarGeorge-Hyslop, Peter S.Peter S.George-HyslopIkezu, TsuneyaTsuneyaIkezuSchilling, StephanStephanSchillingDemuth, Hans-UlrichHans-UlrichDemuthLemere, Cynthia A.Cynthia A.Lemere2022-03-042022-03-042013https://publica.fraunhofer.de/handle/publica/23443710.1016/j.ajpath.2013.05.005Amyloid-v (Av) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 Av), 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 Av peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 Av deposition in humans and animal models. PyroGlu-3 Av immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general Av IR. PyroGlu-3 Av is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 Av deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general Av deposition preceding pyroGlu-3 Av deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 Av is a major species of v-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 Av peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.en610620Pyroglutamate-3 amyloid-v deposition in the brains of humans, non-human primates, canines, and Alzheimer disease-like transgenic mouse modelsjournal article