Article

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

The Mental Health Research Institute, Parkville, VIC, Australia.
The international journal of biochemistry & cell biology (Impact Factor: 4.24). 12/2010; 42(12):1915-8. DOI: 10.1016/j.biocel.2010.08.015
Source: PubMed

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

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    • "It has been reported that the reduction of N3pE-A␤ by inhibition of glutaminyl cyclase, an enzyme responsible for N3pE-A␤ formation, results in a decrease in total plaque load in transgenic mouse models of AD [15]. Because N3pE-A␤ has been known to have a higher propensity for stability than full-length N-terminal A␤ [14], N3pE-A␤-positive plaques may be resistant to degradation. We therefore proposed that N3pE-A␤ does not act as a seed for initiating plaque formation but as a site for further accumulation of A␤ in amyloid plaques, thereby accelerating their growth. "
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    • "Oligomers of modified forms of N-terminally truncated A peptides having pyroglutamate as first residue in the sequence (pE-A) have also been detected in the cerebral cortex of AD patients (Piccini et al., 2005). pE-A peptides are believed to play an important role in the pathogenesis of AD because they are highly abundant in the brains of AD patients and they are major constituents of the amyloid plaques (for a recent review, see Gunn et al., 2010). In vitro studies indicate that pE-A peptides are more aggregation prone and neurotoxic than full length A (Harigaya et al., 2000; Russo et al., 2002). "
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