N-Terminal pyroglutamate formation of Aß38 and Aß40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation.
J Neurochem
; 121(5): 774-84, 2012 Jun.
Article
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| MEDLINE
| ID: mdl-22375951
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-ß protein Aß37, Aß38, Aß40, Aß42 and ADan species in vitro, which were modified by N-terminal pGlu (pGlu-Aß3-x, pGlu-ADan) or possess the intact N-terminus (Aß1-x, ADan). The pGlu-modification confers rapid formation of oligomers and short fibrillar aggregates. In accordance with these observations, the pGlu-modified Aß38, Αß40 and Αß42 species inhibit hippocampal long term potentiation of synaptic response, but pGlu-Aß3-42 showing the highest effect. Among the unmodified Aß peptides, only Aß1-42 exhibites such propensity, which was similar to pGlu-Aß3-38 and pGlu-Aß3-40. 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 Aß1-x, Aß3-x or N-truncated pGlu-Aß3-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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácido Pirrolidona Carboxílico
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Péptidos beta-Amiloides
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Potenciación a Largo Plazo
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Enfermedad de Alzheimer
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Hipocampo
Límite:
Animals
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Humans
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Male
Idioma:
En
Revista:
J Neurochem
Año:
2012
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Reino Unido