N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation
N-Terminal pyroglutamate formation of Aβ38 and Aβ40 enforces oligomer formation and potency to disrupt hippocampal long-term potentiation
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DOI：
10.1111/j.1471-4159.2012.07707.x
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发表时间：
2012-06-01
影响因子：
4.7
通讯作者：
Demuth, Hans-Ulrich
中科院分区：
文献类型：
--
作者：
Schlenzig, Dagmar;Roenicke, Raik;Demuth, Hans-Ulrich
J. Neurochem. (2012) 121, 774784. Abstract Pyroglutamate (pGlu)-modified amyloid peptides have been identified in sporadic and familial forms of Alzheimers disease (AD) and the inherited disorders familial British and Danish Dementia (FBD and FDD). In this study, we characterized the aggregation of amyloid-beta protein A beta 37, A beta 38, A beta 40, A beta 42 and ADan species in vitro, which were modified by N-terminal pGlu (pGlu-A beta 3-x, pGlu-ADan) or possess the intact N-terminus (A beta 1-x, ADan). The pGlu-modification confers rapid formation of oligomers and short fibrillar aggregates. In accordance with these observations, the pGlu-modified A beta 38, ?beta 40 and ?beta 42 species inhibit hippocampal long term potentiation of synaptic response, but pGlu-A beta 3-42 showing the highest effect. Among the unmodified A beta peptides, only A beta 1-42 exhibites such propensity, which was similar to pGlu-A beta 3-38 and pGlu-A beta 3-40. 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 A beta 1-x, A beta 3-x or N-truncated pGlu-A beta 3-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.
