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

https://doi.org/10.1016/j.biocel.2010.08.015Get rights and content

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.

Introduction

Amyloid-beta (Aβ), the major protein constituent of the amyloid plaques in Alzheimer's disease (AD), is derived from the proteolytic cleavage of a type I integral membrane protein termed amyloid precursor protein (APP). Rather than a distinct species, brain Aβ collectively represents a family of hydrophobic, 30–43 amino acid peptides, possessing extensive heterogeneity in both the amino- and carboxy-terminal sequence (Harigaya et al., 2000, Portelius et al., 2010). Whilst the biological function of Aβ (if any) remains speculative, there is much evidence implicating the various isoforms of Aβ as the neurotoxic agents underlying cellular degeneration, inflammation and cognitive decline in AD. Historically, this heterogeneity in the terminal regions of Aβ led to inconsistent findings regarding the primary structure of Aβ in plaques; several groups reported an inability to establish sequence information due to an N-terminus that was ‘blocked’ from Edman degradation (Masters et al., 1985, Selkoe et al., 1986). The proteolytically resistant N-terminus was later determined to be a pyroglutamate residue, resulting from the intramolecular dehydration of an exposed glutamate at position 3 or 11 (Mori et al., 1992).

Pyroglutamate-Abeta (pE-Aβ) is highly abundant in the brains of AD and Down's syndrome patients, differentiating these brains from those of normal-aged controls where the majority of Aβ has an intact N-terminus (Piccini et al., 2005). Analysis of the spectrum of Aβ isoforms deposited in brain tissue has revealed that pE-Aβ represents approximately 25% of total Aβ in virtually every AD brain (Harigaya et al., 2000). Furthermore, N-terminally truncated Aβ increases with disease progression by approximately 20% from Braak stages IV–VI (Guntert et al., 2006) and collectively accounts for the majority of deposited Aβ (up to 60%). In contrast, cored plaques from cognitively normal pathologic aging patients contain mainly full-length peptide (Aβ1–42), while compact plaques from vascular amyloid consist mainly of Aβ1–40 (Guntert et al., 2006).

Section snippets

Structure

Pyroglutamate-Aβ formation is a multi-step process requiring as a substrate amino-terminally truncated Aβ beginning at glutamate 3 or 11, followed by the cyclisation of exposed glutamate to pyroglutamate (Fig. 1). This process results in the loss of 3 charges for Aβ3pE, and 6 charges for Aβ11pE, consequently increasing hydrophobicity, and promoting rapid adoption of β-sheet structures and toxic aggregate formation (He and Barrow, 1999, Schilling et al., 2006). Importantly however, pE-Aβ is

Expression, activation and turnover

The origin(s) of amino-truncated Aβ substrates for pyroglutamate formation are not well understood. The loss of Asp-Ala preceding the glutamate at position 3 is necessary for Aβ3pE formation; however, it is unclear whether this truncated precursor is directly liberated from APP by endoproteolysis (Fig. 2), or the full-length Aβ is post-translationally processed by aminopeptidases. The former is thought to be the case for generation of the Aβ11pE precursor by β-secretase cleavage of APP to

Biological and pathophysiological functions

Aβ has been most routinely investigated as a cause of injury and death of neuronal cells and is believed to be a central contributor to neurodegeneration in AD, yet there are arguments against a purely pathological role for Aβ. These roles may include down-regulating synaptic activity to prevent excitotoxicity, altering the functional expression of neuronal ion channels, and even acting as a neurotrophic factor at low concentrations (see Pearson and Peers, 2006, for review).

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Possible medical applications

The prevalence of N-terminally truncated and pE-Aβ isoforms in the AD brain has drawn attention to mouse models of Aβ accumulation commonly used in AD research. The Tg2576 mouse line is used extensively for AD modelling and testing of potential therapeutics. However, rather than the spectrum of N-truncated Aβ species found in human AD brain, N-truncated and pE forms of insoluble Aβ appear to account for only 5% of total Aβ in Tg2576 mice, and then only in very old (16–23 months) mice (

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