N‐Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long‐term potentiation

Abstract

J. Neurochem. (2012) 121, 774–784. Abstract Pyroglutamate (pGlu)‐modified amyloid peptides have been identified in sporadic and familial forms of Alzheimer’s disease (AD) and the inherited disorders familial British and Danish Dementia (FBD and FDD). In this study, we characterized the aggregation of amyloid‐β protein Aβ37, Aβ38, Aβ40, Aβ42 and ADan species in vitro, which were modified by N‐terminal pGlu (pGlu‐Aβ3‐x, pGlu‐ADan) or possess the intact N‐terminus (Aβ1‐x, ADan). The pGlu‐modification confers rapid formation of oligomers and short fibrillar aggregates. In accordance with these observations, the pGlu‐modified Aβ38, Αβ40 and Αβ42 species inhibit hippocampal long term potentiation of synaptic response, but pGlu‐Aβ3‐42 showing the highest effect. Among the unmodified Aβ peptides, only Aβ1‐42 exhibites such propensity, which was similar to pGlu‐Aβ3‐38 and pGlu‐Aβ3‐40. Likewise, the amyloidogenic peptide pGlu‐ADan impaired synaptic potentiation more pronounced than N‐terminal unmodified ADan. The results were validated using conditioned media from cultivated HEK293 cells, which express APP variants favoring the formation of Aβ1‐x, Aβ3‐x or N‐truncated pGlu‐Aβ3‐x species. Hence, we show that the ability of different amyloid peptides to impair synaptic function apparently correlates to their potential to form oligomers as a common mechanism. The pGlu‐modification is apparently mediating a higher surface hydrophobicity, as shown by 1‐anilinonaphtalene‐8‐sulfonate fluorescence, which enforces potential to interfere with neuronal physiology.

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Two key observations support this theory: 1) familial AD mutations in APP elevate the expression of Aβ1-42 [24,25]; and 2) Aβ1-42 is more prone to aggregation and is more toxic than Aβ1-40 [26,27]. However, it was reported that pyroglutamate-Aβ, which is also presented in AD plaques, could also be the toxic isoform of Aβ [28][29][30][31]. Pyroglutamate-Aβ is more prone to aggregation compared with Aβ1-42 [29].…”

“…However, it was reported that pyroglutamate-Aβ, which is also presented in AD plaques, could also be the toxic isoform of Aβ [28][29][30][31]. Pyroglutamate-Aβ is more prone to aggregation compared with Aβ1-42 [29]. Mice overexpressing this peptide showed a selective hippocampal neurodegeneration [31], and passive immunization against this peptide reduces the amyloid burden in an APP/PS1 double-transgenic mouse model [30].…”

Expression, purification and initial characterization of human meprin β from Pichia pastoris

“…Thus, meprin β might be involved in the generation of potentially more toxic species of Aβ, especially in the formation of Aβ3-40/42, which, in turn, is converted by glutaminyl cyclase into the aggregation prone pGlu3-Aβ. This Aβ species is targeted currently in clinical trials [11][12][13][14].…”

CuII Binding to Various Forms of Amyloid‐β Peptides: Are They Friends or Foes?

“…[116,117] These peptides are considered to be more toxic than the full-length ones, [118][119][120][121][122][123][124][125][126][127][128][129][130][131] given their connection to modified plaque morphology, hampered degradation of the pyroglutamate forms, higher propensity to form -sheets, and impact on the process of aggregation of the full-length peptides. The formation of pyroglutamate at the 11-position (see above) is also possible, but its effect has been less studied.…”