Pyroglutamate-3 Amyloid-β Deposition in the Brains of Humans, Non-Human Primates, Canines, and Alzheimer Disease-Like Transgenic Mouse Models

Amyloid-beta (A beta) peptides, starting with pyroglutamate at the third residue (pyroGlu-3 A beta), 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 A beta peptides. Here, we report the first comprehensive and comparative IHC evaluation of pyroGlu-3 A beta deposition in humans and animal models. PyroGlu-3 A beta immunoreactivity (IR) is abundant in plaques and cerebral amyloid angiopathy of AD and Down syndrome patients, colocalizing with general A beta IR. PyroGlu-3 A beta is further present in two nontransgenic mammalian models of cerebral amyloidosis, Caribbean vervets, and beagle canines. In addition, pyroGlu-3 A beta deposition was analyzed in 12 different AD-like transgenic mouse models. In contrast to humans, all transgenic models showed general All deposition preceding pyroGlu-3 A beta deposition. The findings varied greatly among the mouse models concerning age of onset and cortical brain region. In summary, pyroGlu-3 A beta is a major species of beta-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 A beta peptides for the development of human AD pathology, this study provides insights into the usage of animal models in AD studies.