Pyroglutamate-Aβ: Role in the natural history of Alzheimer's disease

The accumulation of amyloid-beta (A beta) peptides is believed to be a central contributor to the neurodegeneration typically seen in Alzheimer's disease (AD) brain. A beta extracted from AD brains invariably possesses extensive truncations, yielding peptides of differing N- and C-terminal composition. Whilst A beta is often abundant in the brains of cognitively normal elderly people, the brains of AD patients are highly enriched for N-terminally truncated A beta bearing the pyroglutamate modification. Pyroglutamate-A beta (pE-A beta) has a higher propensity for oligomerisation and aggregation than full-length A beta, potentially seeding the accumulation of neurotoxic A beta oligomers and amyloid deposits. In addition, pE-A beta has increased resistance to clearance by peptidases, causing these peptides to persist in biological fluids and tissues. The extensive deposition of pE-A beta in human AD brain is under-represented in many transgenic mouse models of AD, reflecting major differences in the production and processing of A beta peptides in these models compared to the human disease state. (C) 2010 Elsevier Ltd. All rights reserved.