Neuroinflammation has a major role in several brain disorders including Alzheimer’s disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone–pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer’s disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.

Anti-HLA-antibody characteristics aid to risk-stratify patients and improve long-term renal graft outcomes. Complement activation by donor-specific antibody (DSA) is an important characteristic that may determine renal allograft outcome. There is heterogeneity in graft outcomes within the moderate to high immunological risk cases (cross-match-positive). We explored the role of C3d-positive DSAs in sub-stratification of cross-match-positive cases and relate to the graft outcomes. We investigated 139 cross-match-positive living-donor renal transplant recipients from four transplant centres in the United Kingdom. C3d assay was performed on serum samples obtained at pretreatment (predesensitization) and Day 14 post-transplant. C3d-positive DSAs were found in 52 (37%) patients at pretreatment and in 37 (27%) patients at Day 14 post-transplant. Median follow-up of patients was 48 months (IQR 20.47-77.57). In the multivariable analysis, pretreatment C3d-positive DSA was independently associated with reduced overall graft survival, the hazard ratio of 3.29 (95% CI 1.37-7.86). The relative risk of death-censored five-year graft failure was 2.83 (95% CI 1.56-5.13). Patients with both pretreatment and Day 14 C3d-positive DSAs had the worst five-year graft survival at 45.5% compared with 87.2% in both pretreatment and Day 14 C3d-negative DSA patients with the relative risk of death-censored five-year graft failure was 4.26 (95% CI 1.79, 10.09). In this multicentre study, we have demonstrated for the first time the utility of C3d analysis as a distinctive biomarker to sub-stratify the risk of poor graft outcome in cross-match-positive living-donor renal transplantation.

Tauopathy features in many neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP‐17), where aggregation of misfolded and hyperphosphorylated tau impairs cytoplasmic function and axonal transport, and ultimately leads to cell death. Common complications in patients with FTDP‐17 include upper airway dysfunctions such as swallowing and voice disorders and mutism, and in previous work we demonstrated that upper airway and swallowing complications also occur in a mouse model of FTDP‐17 carrying the P301L mutation. Because of these complications, we investigated: 1) Whether Tau‐P301L transgenic mice also have impaired vocalization, owing to vocalization requiring expiratory airflow through the larynx; and 2) The underlying pathology in Tau‐P301L mice linking irregular vocal patterns to tauopathy.Male Tau‐P301L mice on an FVB/N background interacted with a female wildtype (WT) mouse in estrous for 5 minutes, during which ultrasonic vocalizations (USV) were recorded (UltraSoundGate condensor microphone, Avisoft Berlin, Germany). USV recordings were obtained from Tau‐P301L and wild‐type mice aged 3, 5, 7 and 9 months. In parallel, social interactivity was also monitored. While a trend for a lower number and duration of USV and a higher frequency of USV was observed in Tau‐P301L mice, USV in both Tau‐P301L and WT mice were diverse, with the large variance in the number, duration and frequency of vocalizations in Tau‐P301L and WT mice indicating no statistical difference between groups. However, in each age group, the number and duration of USV in a subpopulation of Tau‐P301L mice was lower than and outside the range of WT mice. In these Tau‐P301L mice, 80% of calls were less than 45 msec duration (vs 55% in WT), while 20% of calls were greater than 45 msec duration (vs 45% in WT). The same subpopulation of Tau‐P301L mice displayed a decreased complexity (frequency modulation) and repertoire (call types) of USV compared to WT. These changes to USV in a subpopulation of Tau‐P301L mice were already present in mice aged 3 months, and the parameters measured deteriorated with age. Immunohistochemical analysis identified presence of anti‐human PHF‐Tau (clone AT8, ThermoScientific) and anti‐tau phosphoserine 199/202 (Millipore) immunoreactivity in cell bodies of upper airway and vocalization‐related brain nuclei, including the Periaqueductal Gray (PAG), Nucleus Ambiguus and Kölliker Fuse (KF) nuclei. Further, compared to WT, 40% fewer forkhead box protein P2 (FOXP2) immunoreactive cell bodies were present in the KF of 9‐month‐old Tau‐P301L mice, while the number of FOXP2 immunoreactive cells in the PAG was similar.Our data indicate: 1) an early onset of vocalization disorder in a subpopulation of Tau‐P301L mice; 2) a deterioration in USV that progresses as Tau‐P301L mice age; and 3) presence of tauopathy and neurodegeneration in brain regions that regulate the upper airways and vocalization. Our results also provide a base for examining whether vocalization/voice disturbances are a potential ‘early’ detection diagnostic for dementia.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.