N-terminally truncated Ab peptides constitute a major part of A� accumulating in Alzheimers disease (AD). In particular, pyroglutamate (pE, pGlu)�modified A�, A�3pE-40/42 and A�11pE-40/42, have been shown to correlate with disease progression and being overrepresented in early-onset forms of inherited AD. Recently, we could show that A�3pE-40/42 form oligomeric structures with considerable surface hydrophobicity which, in turn, mediates a significantly enhanced neurotoxicity. Glutaminyl cyclase (QC, isoQC) has been identified to catalyze the conversion of glutamic acid into pGlu, thereby mediating the formation of pE-Ab. QCs represent single-zinc metalloenzymes, which are localized in the secretory pathway of mammalian cells. QC activity is particularly high in neuronal tissue. In addition, the enzyme expression is further upregulated in human AD, thus correlating with appearance of pE-A�. The crucial involvement of QC in pE-A� formation has been genetically validated in transgenic mouse models with AD-like pathology. The cognitive deficits correlated with the amount of A�3pE-42, which could be modulated by knock-out or overexpression of QC.  These data make QC-inhibition an atractive therapeutic approach. Probiodrug is developing competitive inhibitors of QC in order to suppress the formation of A�3pE-40/42 and A�11pE-40/42. The treatment of transgenic mice with PQ912 attenuated the pE-A� pathology and ameliorated behavioral impairment in prophylactic as well as therapeutic settings. PQ912 is the first QC-inhibitor being applied to humans,  has nearly completed  Phase I  being very safe with an attractive PK/PD profile and is ready to go into patient studies

Inhibitors of glutaminyl cyclase prevent pE-A� mediated neurotoxicity: A new concept for the treatment of Alzheimer's disease

246th National Meeting (2013)

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