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

Amyloid-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.