Identification of N-Terminally Truncated Pyroglutamate Amyloid-β in Cholesterol-Enriched Diet-Fed Rabbit and AD Brain

The main amyloid-beta peptide (A beta) variants detected in the human brain are A beta(1-40) and A beta(1-42); however, a significant proportion of A beta in Alzheimer's disease (AD) brain also consists of N-terminal truncated/modified species. A beta N3(pE), A beta peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular A beta deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular A beta accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of A beta N3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected A beta N3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting A beta peptides in a suitable non-transgenic animal model.