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Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology.

Abstract：

:Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified Abeta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease. We found that the N-terminal pE-formation is catalyzed by glutaminyl cyclase in vivo. Glutaminyl cyclase expression was upregulated in the cortices of individuals with Alzheimer's disease and correlated with the appearance of pE-modified Abeta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced Abeta(3(pE)-42) burden in two different transgenic mouse models of Alzheimer's disease and in a new Drosophila model. Treatment of mice was accompanied by reductions in Abeta(x-40/42), diminished plaque formation and gliosis and improved performance in context memory and spatial learning tests. These observations are consistent with the hypothesis that Abeta(3(pE)-42) acts as a seed for Abeta aggregation by self-aggregation and co-aggregation with Abeta(1-40/42). Therefore, Abeta(3(pE)-40/42) peptides seem to represent Abeta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-Abeta by inhibition of glutaminyl cyclase offers a new therapeutic option for the treatment of Alzheimer's disease and provides implications for other amyloidoses, such as familial Danish dementia.

journal_name

Nat Med

journal_title

Nature medicine

authors

Schilling S,Zeitschel U,Hoffmann T,Heiser U,Francke M,Kehlen A,Holzer M,Hutter-Paier B,Prokesch M,Windisch M,Jagla W,Schlenzig D,Lindner C,Rudolph T,Reuter G,Cynis H,Montag D,Demuth HU,Rossner S

doi

10.1038/nm.1872

subject

Has Abstract

pub_date

2008-10-01 00:00:00

pages

1106-11

issue

10

eissn

1078-8956

issn

1546-170X

pii

nm.1872

journal_volume

14

pub_type

杂志文章

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