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.
Introducing customers to new ideas lies at the heart of marketing, yet surprisingly little is known about customers’ state of inspiration within this domain. This article reviews prior conceptualizations of general inspiration in psychology and introduces the concept of customer inspiration as a customer's temporary motivational state that facilitates the transition from the reception of a marketing-induced idea to the intrinsic pursuit of a consumption-related goal. The authors develop and validate a two-state, ten-item customer inspiration scale that consists of inspired-by and inspired-to states. The scale development process begins with item generation, followed by five studies: (1) scale purification and initial validation, (2) exploration of the nomological network, (3) tests for the experimental and predictive validity, (4) replication within a field experiment, and (5) assessments of generalizability and boundary conditions. Empirical results reveal sound psychometric properties of the scale, demonstrate its unique position in relation to established marketing constructs, and support experimental and predictive validity. Applying the scale in marketing practice offers a new way for firms to increase demand, motivate customers’ exploration behavior, and build customer loyalty.
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