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

被引：41

作者：

Brendel, M. ^{[1
]}

Jaworska, A. ^{[2
,3
]}

Herms, J. ^{[2
,4
]}

Trambauer, J. ^{[5
]}

Roetzer, C. ^{[1
]}

Gildehaus, F-J ^{[1
]}

Carlsen, J. ^{[1
]}

Cumming, P. ^{[6
]}

Bylund, J. ^{[7
]}

Luebbers, T. ^{[8
]}

Bartenstein, P. ^{[1
,4
]}

Steiner, H. ^{[2
,5
]}

Haass, C. ^{[2
,4
,5
]}

Baumann, K. ^{[9
]}

Rominger, A. ^{[1
,4
]}

机构：

[1] Univ Munich, Dept Nucl Med, D-81377 Munich, Germany

[2] DZNE German Ctr Neurodegenerat Dis, Munich, Germany

[3] Int Inst Mol & Cell Biol, Lab Neurodegenerat, Warsaw, Poland

[4] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[5] Univ Munich, Biomed Ctr BMC, D-81377 Munich, Germany

[6] Univ Oslo, Dept Psychiat, Oslo, Norway

[7] F Hoffmann La Roche & Co Ltd, Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Pharmaceut Sci, CH-4002 Basel, Switzerland

[8] F Hoffmann La Roche & Co Ltd, Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Small Mol Res, CH-4002 Basel, Switzerland

[9] F Hoffmann La Roche & Co Ltd, Roche Innovat Ctr Basel, Roche Pharma Res & Early Dev, Neurosci Discovery, CH-4002 Basel, Switzerland

来源：

MOLECULAR PSYCHIATRY | 2015年 / 20卷 / 10期

基金：

欧洲研究理事会;

关键词：

TRANSGENIC MOUSE MODEL; ALZHEIMERS-DISEASE; IN-VIVO; DEPOSITION; TG2576; BRAIN; MICE; MUTATIONS; MEMANTINE; A-BETA-42;

D O I：

10.1038/mp.2015.74

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1179 / 1187

页数：9

共 43 条

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