30 September 2008. If pyroglutamate Aβ sounds like some sort of Alzheimer disease incendiary device, then could inhibitors of the enzyme that sparks pyroglutamate formation extinguish the disease? The metaphor may not be so far-fetched. Writing in the September 28 Nature Medicine online, researchers in Germany and Austria report that inhibitors of glutaminyl cyclase (QC) suppress Aβ pathology and improve learning and memory in various models of the disease. The data suggest that quenching pyroglutamate Aβ may be another viable therapeutic strategy for tackling AD.
The Alzforum has covered most of this story previously when Hans-Ulrich Demuth of the biotech company Probiodrug AG in Halle, Germany, presented preliminary data at this year’s Keystone Symposium on AD in Keystone, Colorado. Demuth reported that pyroglutamate forms of Aβ (pGluAβ) accelerate fibrillogenesis and that switching the glutamate in the third position of Aβ to glutamine, which cyclizes much faster, accelerates AD-like pathology in mice. In addition, giving QC inhibitors to Tg2576 mice, which overproduce Aβ, reduced learning and memory deficits, whether the inhibitor was given before or after the onset of plaque pathology (see ARF related news story). QC inhibition reportedly also worked when given prior to the emergence of plaques in TASD-41 mice, which have particularly high expression of Aβ precursor protein (APP).
In yesterday’s publication, Demuth and colleagues, including researchers at Steffen Rossner’s lab at the University of Leipzig, Germany, report in addition that the QC inhibitor PBD 150 protects older TASD-41 mice, improving performance in a test of contextual fear. The compound reduces by 75 percent Aβ deposits in a transgenic fly model. In these animals, a construct driving expression of a prothyrotropin-releasing hormone/Aβ3(Q)-42 chimera, leads to massive pyrogluAβ3-42 formation when the chimera is cleaved by prohormone convertases.
First author Stephan Schilling and colleagues also report that QC inhibition does not interfere with APP production or with the proteases that purportedly degrade Aβ in vivo, such as insulin degrading enzyme. Animals seemed to tolerate the compound well, having similar weight gain to controls and showing no signs that the chemical accumulates in the brain or other organs. Whether the QC inhibition strategy will pan out as a potential therapy for AD remains to be seen. pGluAβ has been reported to be a major fraction of Aβ in the senile plaques found in the AD brain (see Saido et al., 1995), though in other researchers’ hands it weighs in as a smaller fraction.—Tom Fagan.
Schilling S, Zeitschel U, Hoffman 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 H-U, Rossner S. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nature Medicine 2008, September 28 advanced online publication.