Pyroglutamate Amyloid β (Aβ) Aggravates Behavioral Deficits in Transgenic Amyloid Mouse Model for Alzheimer Disease

Wittnam, Jessica L.; Portelius, Erik; Zetterberg, Henrik; Gustavsson, Mikael K.; Schilling, Stephan; Koch, Birgit; Demuth, Hans‐Ulrich; Blennow, Kaj; Wirths, Oliver; Bayer, Thomas A.

doi:10.1074/jbc.m111.308601

Cited by 79 publications

(111 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The toxicity of pE-A␤ has recently been highlighted in mouse models overexpressing the soluble isoform of QC, demonstrating exacerbated neurodegeneration and behavioral deficits when crossed with mouse lines overexpressing A␤ or amyloid precursor protein transgenes (65,66). The specific targeting of pE-A␤ via inhibition of QC-catalyzed pyroglutamate synthesis has demonstrated promising results; transgenic AD mice treated with a QC inhibitor show reduced plaque load, reduced gliosis, and an improvement in context memory and spatial learning (67).…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Gunn

Wong

Johanssen³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

Pyroglutamate-modified amyloid-␤ (pE-A␤) is a highly neurotoxic amyloid-␤ (A␤) isoform and is enriched in the brains of individuals with Alzheimer disease compared with healthy aged controls. Pyroglutamate formation increases the rate of A␤ oligomerization and alters the interactions of A␤ with Cu 2؉ and lipids; however, a link between these properties and the toxicity of pE-A␤ peptides has not been established. We report here that A␤3pE-42 has an enhanced capacity to cause lipid peroxidation in primary cortical mouse neurons compared with the fulllength isoform (A␤(1-42)). In contrast, A␤(1-42) caused a significant elevation in cytosolic reactive oxygen species, whereas A␤3pE-42 did not. We also report that A␤3pE-42 preferentially associates with neuronal membranes and triggers Ca 2؉ influx that can be partially blocked by the N-methyl-D-aspartate receptor antagonist MK-801. A␤3pE-42 further caused a loss of plasma membrane integrity and remained bound to neurons at significantly higher levels than A␤(1-42) over extended incubations. Pyroglutamate formation was additionally found to increase the relative efficiency of A␤-dityrosine oligomer formation mediated by copper-redox cycling.A␤ 3 peptides are found in every human brain; however, the concentration and composition of A␤ peptide isoforms are distinctly different in healthy individuals and people with AD (1-3). Amino-truncated A␤ peptides are abundant in the AD brain (4, 5) and increase in prevalence with disease progression (6). The process of A␤ amino-truncation can occur via the actions of aminopeptidases on full-length A␤ peptides (7, 8), via altered cleavage of amyloid precursor protein in the generation of A␤ (9 -11), and potentially by A␤-copper-redox cycling reactions (12). As a consequence, aminotruncation can expose glutamate residues (positions 3 and 11 of A␤) to cyclization by the action of glutaminyl cyclase (QC), forming the highly amyloidogenic pyroglutamate-A␤ (pE-A␤) peptides A␤3pE-40, A␤3pE-42, A␤11pE-40, and A␤11pE-42 (7, 13).Pyroglutamate formation significantly increases the hydrophobicity of A␤, causing the peptide to aggregate more rapidly and form oligomers at lower concentration thresholds (5, 14, 15). pE-A␤ peptides also demonstrate increased ␤-sheet (aggregate structure) stability (16, 17), differences in fibril ultrastructure (18,19), and altered interactions with copper ions (20, 21) and synthetic lipid membranes (22, 23). Notably, trace quantities of A␤3pE-42 have been observed to dramatically enhance the aggregation and neurotoxicity of A␤(1-42) (24), prompting descriptions of pE-A␤ as "prionlike." Still, it remains unclear as to the cytotoxic potency of pE-A␤ peptides compared with their full-length A␤ counterparts. Some studies have demonstrated pE-A␤ peptides to have enhanced toxicity (24 -26), although others have reported no difference in toxicity between the isoforms (27-30). Methodological differences may account somewhat for variability in the relative toxicities reported (Table 1), yet molecular mechanisms to explain...

show abstract

Section: Discussionmentioning

confidence: 99%

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

Gunn

Wong

Johanssen³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The self-assembly of Aβ from soluble monomers into oligomers and, ultimately, amyloid fi brils can be infl uenced not only by the concentrations of Aβ peptides but also by their biochemical modifi cations such as mutations, truncations and pyroglutamate modifi cations (Morgado and Faendrich 2011 ;Wittnam et al 2012 ), as well as by solvent composition, ionic conditions (Klement et al 2007 ;Garvey et al 2011 ) and a wide range of other factors including lipids (Terzi et al 1995(Terzi et al , 1997Butterfi eld and Lashuel 2010 ). The combination of the hydrophilic N-terminal segment and a highly hydrophobic C-terminal tail renders amphipathic properties to Aβ and confers its limited aqueous solubility, high aggregation propensity, and ability to interact with various lipids and their assemblies.…”

Section: Interactions Of Aβ With Lipids Surfaces: Electrostatic Effectsmentioning

confidence: 99%

Lipids in Amyloid-β Processing, Aggregation, and Toxicity

Morgado

Garvey

2015

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Aggregation of amyloid-beta (Aβ) peptide is the major event underlying neuronal damage in Alzheimer's disease (AD). Specific lipids and their homeostasis play important roles in this and other neurodegenerative disorders. The complex interplay between the lipids and the generation, clearance or deposition of Aβ has been intensively investigated and is reviewed in this chapter. Membrane lipids can have an important influence on the biogenesis of Aβ from its precursor protein. In particular, increased cholesterol in the plasma membrane augments Aβ generation and shows a strong positive correlation with AD progression. Furthermore, apolipoprotein E, which transports cholesterol in the cerebrospinal fluid and is known to interact with Aβ or compete with it for the lipoprotein receptor binding, significantly influences Aβ clearance in an isoform-specific manner and is the major genetic risk factor for AD. Aβ is an amphiphilic peptide that interacts with various lipids, proteins and their assemblies, which can lead to variation in Aβ aggregation in vitro and in vivo. Upon interaction with the lipid raft components, such as cholesterol, gangliosides and phospholipids, Aβ can aggregate on the cell membrane and thereby disrupt it, perhaps by forming channel-like pores. This leads to perturbed cellular calcium homeostasis, suggesting that Aβ-lipid interactions at the cell membrane probably trigger the neurotoxic cascade in AD. Here, we overview the roles of specific lipids, lipid assemblies and apolipoprotein E in Aβ processing, clearance and aggregation, and discuss the contribution of these factors to the neurotoxicity in AD.

show abstract

“…Plaque load quantification was performed as described previously (65). For quantification of astrogliosis and microgliosis, sections were stained with anti-GFAP and anti-IBA1 and analyzed likewise.…”

mentioning

confidence: 99%