Pyroglutamate-Aβ: Role in the natural history of Alzheimer's disease
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.
Available from: Minho Moon
- "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 . Because N3pE-A␤ has been known to have a higher propensity for stability than full-length N-terminal A␤ , 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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ABSTRACT: One of the major hallmarks of Alzheimer's disease (AD) is the extracellular deposition of amyloid-β (Aβ) as senile plaques in specific brain regions. Clearly, an understanding of the cellular processes underlying Aβ deposition is a crucial issue in the field of AD research. Recent studies have found that accumulation of intraneuronal Aβ (iAβ) is associated with synaptic deficits, neuronal death, and cognitive dysfunction in AD patients. In this study, we found that Aβ deposits had several shapes and sizes, and that iAβ occurred before the formation of extracellular amyloid plaques in the subiculum of 5XFAD mice, an animal model of AD. We also observed pyroglutamate-modified Aβ (N3pE-Aβ), which has been suggested to be a seeding molecule for senile plaques, inside the Aβ plaques only after iAβ accumulation, which argues against its seeding role. In addition, we found that iAβ accumulates in calcium-binding protein (CBP)-free neurons, induces neuronal death, and then develops into senile plaques in 2-4-month-old 5XFAD mice. These findings suggest that N3pE-Aβ-independent accumulation of Aβ in CBP-free neurons might be an early process that triggers neuronal damage and senile plaque formation in AD patients. Our results provide new insights into several long-standing gaps in AD research, namely how Aβ plaques are formed, what happens to iAβ and how Aβ causes selective neuronal loss in AD patients.
Available from: Silvia Campioni
- "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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ABSTRACT: Senile plaques (SP) are characteristic histopathological manifestations of Alzheimer's disease (AD), but are also found in normal aging (NA). Recent studies have demonstrated that beta amyloid (Aβ) proteins that have been truncated at the N-terminal position 3 (AβpN3) are the predominant component of SP in AD, but not in NA. The present study revealed that AβpN3 was deposited in an age-dependent manner in canine brains. Moreover, AβpN3 was the main component of the SP that developed in very old dogs. The deposition of AβpN3 increased in accordance with the number of SP, but that of N-terminally intact Aβ (AβN1) did not. In addition, AβpN3 was also deposited in the SP of a Japanese macaque and an American black bear, but not in a feline brain. Focal microvascular cerebral amyloid angiopathy was also observed in the deep cortices and the white matter of the dogs and a woodpecker. Those were always composed of both AβpN3 and AβN1. In conclusion, though non-human animals do not develop full pathology of AD of the human type, AβpN3 is widely deposited in the brains of senescent vertebrates.
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