Amyloid-PET predicts inhibition of de novo plaque formation upon chronic gamma-secretase modulator treatment

作者：Brendel M; Jaworska A; Herms J; Trambauer J; Roetzer C; Gildehaus F J; Carlsen J; Cumming P; Bylund J; Luebbers T; Bartenstein P; Steiner H; Haass C; Baumann K; Rominger A^*

来源：Molecular Psychiatry, 2015, 20(10): 1179-1187.

DOI：10.1038/mp.2015.74

In a positron-emission tomography (PET) study with the beta-amyloid (A beta) tracer [F-18]-florbetaben, we previously showed that A beta deposition in transgenic mice expressing Swedish mutant APP (APP-Swe) mice can be tracked in vivo. gamma-Secretase modulators (GSMs) are promising therapeutic agents by reducing generation of the aggregation prone A beta(42) species without blocking general.-secretase activity. We now aimed to investigate the effects of a novel GSM [8-(4-Fluoro-phenyl)-[1,2,4] triazolo[1,5-a] pyridin-2-yl]-[1-(3-methyl-[1,2,4] thiadiazol-5-yl)-piperidin-4-yl]-amine (RO5506284) displaying high potency in vitro and in vivo on amyloid plaque burden and used longitudinal A beta-microPET to trace individual animals. Female transgenic (TG) APP-Swe mice aged 12 months (m) were assigned to vehicle (TG-VEH, n = 12) and treatment groups (TG-GSM, n = 12), which received daily RO5506284 (30 mg kg(-1)) treatment for 6 months. A total of 131 A beta-PET recordings were acquired at baseline (12 months), follow-up 1 (16 months) and follow-up 2 (18 months, termination scan), whereupon histological and biochemical analyses of A beta were performed. We analyzed the PET data as VOI-based cortical standard-uptake-value ratios (SUVR), using cerebellum as reference region. Individual plaque load assessed by PET remained nearly constant in the TG-GSM group during 6 months of RO5506284 treatment, whereas it increased progressively in the TG-VEH group. Baseline SUVR in TG-GSM mice correlated with Delta%-SUVR, indicating individual response prediction. Insoluble A beta(42) was reduced by 56% in the TG-GSM versus the TG-VEH group relative to the individual baseline plaque load estimates. Furthermore, plaque size histograms showed differing distribution between groups of TG mice, with fewer small plaques in TG-GSM animals. Taken together, in the first A beta-PET study monitoring prolonged treatment with a potent GSM in an AD mouse model, we found clear attenuation of de novo amyloidogenesis. Moreover, longitudinal PET allows non-invasive assessment of individual plaque-load kinetics, thereby accommodating inter-animal variations.

• 出版日期2015-10