Detection of peri-synaptic amyloid-ß pyroglutamate aggregates in early stages of Alzheimer's disease and in AßPP transgenic mice using a novel monoclonal antibody.

ABSTRACT

The neurodegenerative pathology in patients with Alzheimer's disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-ß (Aß) species. Among them, recent studies indicate that the pyroglutamate modification of Aß (pE(3)Aß) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aß aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aß across the spectrum of AD and in the brains of amyloid-ß protein precursor (AßPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated D129) that specifically recognizes pE(3)Aß and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AßPP tg mice. We found that in early stages of AD and young AßPP tg mice pE(3)Aß was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AßPP tg mice, pE(3)Aß was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aß might contribute to early cognitive dysfunction in AD.