Evaluation of Small-Animal PET Outcome Measures to Detect Disease Modification Induced by BACE Inhibition in a Transgenic Mouse Model of Alzheimer Disease

Abstract

In this study, we investigated the effects of chronic administration of an inhibitor of the b-site amyloid precursor protein-cleaving enzyme 1 (BACE1) on Alzheimer-related pathology by multitracer PET imaging in transgenic APPPS1-21 (TG) mice. Methods: Wild-type (WT) and TG mice received vehicle or BACE inhibitor (60 mg/kg) starting at 7 wk of age. Outcome measures of brain metabolism, neuroinflammation, and amyloid-b pathology were obtained through small-animal PET imaging with 18 F-FDG, 18 F-peripheral benzodiazepine receptor ( 18 F-PBR), and 18 F-florbetapir ( 18 F-AV45), respectively. Baseline scans were acquired at 6-7 wk of age and follow-up scans at 4, 7, and 12 mo. 18 F-AV45 uptake was measured at 8 and 13 mo of age. After the final scans, histologic measures of amyloid-b (4G8), microglia (ionized calcium binding adaptor molecule 1), astrocytes (glial fibrillary acidic protein), and neuronal nuclei were performed. Results: TG mice demonstrated significant age-associated increases in 18 F-AV45 uptake. An effect of treatment was observed in the cortex (P 5 0.0014), hippocampus (P 5 0.0005), and thalamus (P , 0.0001). Histology confirmed reduction of amyloid-b pathology in TG-BACE mice. Regardless of treatment, TG mice demonstrated significantly lower 18 F-FDG uptake than WT mice in the thalamus (P 5 0.0004) and hippocampus (P 5 0.0332). Neuronal nucleus staining was lower in both TG groups in the thalamus and cortex. 18 F-PBR111 detected a significant age-related increase in TG mice (P , 0.0001) but did not detect the treatment-induced reduction in activated microglia as demonstrated by histology. Conclusion: Although 18 F-FDG, 18 F-PBR111, and 18 F-AV45 all detected pathologic alterations between TG and WT mice, only 18 F-AV45 could detect an effect of BACE inhibitor treatment. However, changes in WT binding of 18 F-AV45 undermine the specificity of this effect.

The β‐secretase (BACE) inhibitor NB‐360 in preclinical models: From amyloid‐β reduction to downstream disease‐relevant effects

“…For brain compound and Aβ40 analysis, see Neumann et al (2015) in the AD brain. In agreement with this, a recent microamyloid-PET study performed in mice with the structurally different BACE-1 inhibitor JNJ-49146981 and using one of the "classical" Aβ PET ligands ( 18 F florbetapir) did not detect any differences between the control and treatment groups (Deleye et al, 2017). However, a longitudinal in vivo two photon microscopy study using methoxy-X04 to label Aβ in APPPS1-tg mice, with 3-month NB-360 treatment during the phase of rapid Aβ deposition, gave a more detailed picture .…”

In vivo molecular imaging of neuroinflammation in Alzheimer's disease

“…Similarly, Deleye et al . () observed significant reductions in [ 18 F]AV‐45 following chronic BACE1 inhibitor treatment, however in contrast to Maeda et al., no alterations in TSPO‐PET were observed. More recently, James et al .…”

“…Intra-hippocampal treatment with anti-Ab antibody showed decreases in [ 11 C] PiB but increases in [ 18 F]FEDAA1106 uptake in the TG mice, indicating that the treatment successfully reduced amyloid burden but was associated with increased neuroinflammation. Similarly, Deleye et al (2017) observed significant reductions in [ 18 F]AV-45 following chronic BACE1 inhibitor treatment, however in contrast to Maeda et al, no alterations in TSPO-PET were observed. More recently, James et al (2017) demonstrated that [ 18 F]GE-180 permitted detection of decreased cortical and hippocampal neuroinflammation in the APP L/S mouse following treatment with LM11A-31, a clinical AD treatment which attenuates tau phosphorylation, neurite degeneration and microglial activation.…”

Systemic immune‐checkpoint blockade with anti‐PD1 antibodies does not alter cerebral amyloid‐β burden in several amyloid transgenic mouse models

“…We sought to confirm the efficacy of anti‐PD1 treatment in a range of different amyloid‐developing transgenic models used extensively for pharmacological testing in our respective groups (Asberom et al, ; Blanchard et al, ; Deleye et al, ; Games et al, ; Hansen et al, ; Janus et al, ). These strains develop amyloid pathology at different rates and can produce amyloid deposits of significant, compact nature (high thioflavine S reactivity: ThyAPP/PS1 M146L, and ThyAPP/PS1 A246E ) or mostly diffuse deposits (PD‐APP) (Table ).…”