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

Because of their abundance, resistance to proteolysis, rapid aggregation and neurotoxicity, N-terminally truncated and, in particular, pyroglutamate (pE)-modified A beta peptides have been suggested as being important in the initiation of pathological cascades resulting in the development of Alzheimer's disease(1-6). 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 A beta. Oral application of a glutaminyl cyclase inhibitor resulted in reduced A beta(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 A beta(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 A beta(3(pE)-42) acts as a seed for A beta aggregation by self-aggregation and co-aggregation with A beta(1-40/42). Therefore, A beta(3(pE)-40/42) peptides seem to represent A beta forms with exceptional potency for disturbing neuronal function. The reduction of brain pE-A beta 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.