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

摘要

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