Follow-up of β-amyloid (Aβ) deposition in transgenic mouse models of Alzheimer disease (AD) would be a valuable translational tool in the preclinical evaluation of potential antiamyloid therapies. This study aimed to evaluate the ability of the clinically used PET tracer ¹¹C-Pittsburgh compound B (¹¹C-PIB) to detect changes over time in Aβ deposition in the brains of living mice representing the APP23, Tg2576, and APP_swe-PS1_dE9 transgenic mouse models of AD. Methods: Mice from each transgenic strain were imaged with 60-min dynamic PET scans at 7−9, 12, 15, and 18−22 mo of age. Regional ¹¹C-PIB retention was quantitated as distribution volume ratios using Logan graphical analysis with cerebellar reference input, as radioactivity uptake ratios between the frontal cortex (FC) and the cerebellum (CB) during the 60-min scan, and as bound-to-free ratios in the late washout phase (40−60 min). Ex vivo autoradiography experiments were performed after the final imaging session to validate ¹¹C-PIB binding to Aβ deposits. Additionally, the presence of Aβ deposits was evaluated in vitro using staining with thioflavin-S and Aβ_1–40, Aβ_1–16, and Aβ_N3(pE) immunohistochemistry. Results: Neocortical ¹¹C-PIB retention was markedly increased in old APP23 mice with large thioflavin-S–positive Aβ deposits. At 12 mo, the Logan distribution volume ratio for the FC was 1.03 and 0.93 (n = 2), increasing to 1.38 ± 0.03 (n = 3) and 1.34 (n = 1) at 18 and 21 mo of age, respectively. An increase was also observed in bound-to-free ratios for the FC between young (7- to 12-mo-old) and old (15- to 22-mo-old) APP23 mice. Binding of ¹¹C-PIB to Aβ-rich cortical regions was also evident in ex vivo autoradiograms of APP23 brain sections. In contrast, no increases in ¹¹C-PIB retention were observed in aging Tg2576 or APP_swe-PS1_dE9 mice in vivo, although in the latter, extensive Aβ deposition was already observed at 9 mo of age with immunohistochemistry. Conclusion: The results suggest that ¹¹C-PIB binding to Aβ deposits in transgenic mouse brain is highly dependent on the AD model and the structure of its Aβ plaques. Longitudinal in vivo ¹¹C-PIB uptake studies are possible in APP23 mice.

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer’s disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [18 F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

Preclinical animal model studies of brain energy metabolism and neuroinflammation in Alzheimer’s disease have produced conflicting results, hampering both the elucidation of the underlying disease mechanism and the development of effective Alzheimer’s disease therapies. Here, we aimed to quantify the relationship between brain energy metabolism and neuroinflammation in the APP/PS1-21 transgenic mouse model of Alzheimer’s disease using longitudinal in vivo¹⁸F-FDG and ¹⁸F-DPA-714) PET imaging and ex vivo brain autoradiography. APP/PS1-21 (TG, n = 9) and wild type control mice (WT, n = 9) were studied longitudinally every third month from age 6 to 15 months with ¹⁸F-FDG and ¹⁸F-DPA-714 with a one-week interval between the scans. Additional TG (n = 52) and WT (n = 29) mice were used for ex vivo studies. In vivo, the ¹⁸F-FDG SUVs were lower and the ¹⁸F-DPA-714 binding ratios relative to the cerebellum were higher in the TG mouse cortex and hippocampus than in WT mice at age 12 to 15 months ( p < 0.05). The ex vivo cerebellum binding ratios supported the results of the in vivo¹⁸F-DPA-714 studies but not the ¹⁸F-FDG studies. This longitudinal PET study demonstrated decreased energy metabolism and increased inflammation in the brains of APP/PS1-21 mice compared to WT mice.

Molecular mechanisms involved in epileptogenesis in the developing brain remain poorly understood. The gene array approach could reveal some of the factors involved by allowing the identification of a broad scale of genes altered by seizures. In this study we used microarray analysis to reveal the gene expression profile of the laser microdissected hippocampal CA1 subregion one week after kainic acid (KA)-induced status epilepticus (SE) in 21-day-old rats, which are developmentally roughly comparable to juvenile children. The gene expression analysis with the Chipster software generated a total of 1592 differently expressed genes in the CA1 subregion of KA-treated rats compared to control rats. The KEGG database revealed that the identified genes were involved in pathways such as oxidative phosporylation (26 genes changed), and long-term potentiation (LTP; 18 genes changed). Also genes involved in Ca²⁺ homeostasis, gliosis, inflammation, and GABAergic transmission were altered. To validate the microarray results we further examined the protein expression for a subset of selected genes, glial fibrillary protein (GFAP), apolipoprotein E (apo E), cannabinoid type 1 receptor (CB1), Purkinje cell protein 4 (PEP-19), and interleukin 8 receptor (CXCR1), with immunohistochemistry, which confirmed the transcriptome results. Our results showed that SE resulted in no obvious CA1 neuronal loss, and alterations in the expression pattern of several genes during the early epileptogenic phase were comparable to previous gene expression studies of the adult hippocampus of both experimental epileptic animals and patients with temporal lobe epilepsy (TLE). However, some changes seem to occur after SE specifically in the juvenile rat hippocampus. Insight of the SE-induced alterations in gene expression and their related pathways could give us hints for the development of new target-specific antiepileptic drugs that interfere with the progression of the disease in the juvenile age group.

Rationale: Neuroinflammation has been associated with different neurological diseases including Alzheimer’s disease (AD). In AD, the translocator protein 18kDa (TSPO) is overexpressed in the activated microglia that surround the β-amyloid plaques. In the current longitudinal study, using a mouse model of AD, we evaluated the association between β-amyloid deposition and neuroinflammation in AD. Methods: To monitor the longitudinal changes in β-amyloid deposition and neuroinflammation, we used in vivo PET imaging and ex vivo autoradiography with ¹¹C-PIB and a TSPO tracer, ¹⁸F-GE-180, in the APP23 mouse model of AD. We also applied immunohistochemistry to study β-amyloid and activated microglia in the mouse brain tissue. Results: From 17 to 26 months of age, the mice showed robust increased binding of ¹¹C-PIB with aging in the frontal cortex, parietotemporal cortex, hippocampus, and thalamus while the increase in ¹⁸F-GE-180 binding with aging was minimal in areas of early amyloidosis such as frontal cortex and hippocampus. A clear positive correlation between β-amyloid deposition and neuroinflammation was detected with ¹¹C-PIB, and ¹⁸F-GE-180 was obtained only in the parietotemporal cortex and thalamus. Conclusion: The neuroinflammation increase detected with ¹⁸F-GE-180 is less than the increase in amyloidosis detected with ¹¹C-PIB. Furthermore, the binding of ¹⁸F-GE-180 plateaus at an earlier stage of pathogenesis whereas the amyloidosis continues to increase. We suggest that TSPO can be a good marker for early pathogenesis detection but not for tracking long-term disease progression.