Neuron Loss and Behavioral Deficits in the TBA42 Mouse Model Expressing N-Truncated Pyroglutamate Amyloid-β3-42.

Abstract

Pyroglutamate-modified amyloid-β (Aβ) at amino acid position three (Aβ(pE3-42)) is gaining considerable attention as a potential key player in the pathogenesis of Alzheimer's disease (AD). Aβ(pE3-42) is abundant in AD brain and has a high aggregation propensity, stability, and cellular toxicity. The aim of the present work was to study the effect of Aβ(pE3-42) expression on neuron loss and associated behavioral deficits using the TBA42 transgenic mouse model. Expression of pyroglutamate Aβ(3-42) triggers hippocampal CA1 neuron loss and behavioral deficits in the TBA42 mouse model. Mice elicited significant neuron death (-35% at the age of 12 months), deficits in the spatial reference memory, working memory, loss of anxiety, and severe motor deficits in an age-dependent manner. These results support a major pathological function of pyroglutamate Aβ in AD.