Aberrantly activated TAK1 links neuroinflammation and neuronal loss in Alzheimer's disease mouse models.

Neuroinflammation is causally associated with Alzheimer's disease (AD) pathology. Reactive glia cells secrete various neurotoxic factors that impair neuronal homeostasis eventually leading to neuronal loss. Although the glial activation mechanism in AD has been relatively well studied, how it perturbs intraneuronal signaling, which ultimately leads to neuronal cell death, remains poorly understood. Here, we report that compound stimulation with the neurotoxic factors TNF and glutamate aberrantly activates neuronal TAK1 (also known as MAP3K7), which promotes the pathogenesis of AD in mouse models. Glutamate-induced Ca2+ influx shifts TNF signaling to hyper-activate TAK1 enzymatic activity through Ca2+/calmodulin-dependent protein kinase II, which leads to necroptotic cellular damage. Genetic ablation and pharmacological inhibition of TAK1 ameliorated AD-associated neuronal loss and cognitive impairment in the AD model mice. Our findings provide a molecular mechanism linking cytokines, Ca2+ signaling and neuronal necroptosis in AD.

Galantamine suppresses α-synuclein aggregation by inducing autophagy via the activation of α7 nicotinic acetylcholine receptors.

Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders characterized by the aberrant accumulation of α-synuclein (α-syn). Although no treatment is effective for synucleinopathies, the suppression of α-syn aggregation may contribute to the development of numerous novel therapeutic targets. Recent research revealed that nicotinic acetylcholine (nACh) receptor activation has neuroprotective effects and promotes the degradation of amyloid protein by activating autophagy. In an in vitro human-derived cell line model, we demonstrated that galantamine, the nAChR allosteric potentiating ligand, significantly reduced the cell number of SH-SY5Y cells with intracellular Lewy body-like aggregates by enhancing the sensitivity of α7-nAChR. In addition, galantamine promoted autophagic flux, and prevented the formation of Lewy body-resembled aggregates. In an in vivo synucleinopathy mouse model, the propagation of α-syn aggregation in the cerebral cortex was inhibited by galantamine administration for 90 days. These results suggest that α7-nAChR is expected to be a novel therapeutic target, and galantamine is a potential agent for synucleinopathies.

A Pilot, Open-Label Study to Evaluate the Efficacy of Intra-Articular Administration of a Caninized TNF Receptor Fc Fusion Protein as a Treatment for Osteoarthritis-Associated Joint Pain.

Tumor necrosis factor-α (TNF-α) is a potential target for osteoarthritis (OA) treatment. In several recent clinical studies in human OA, anti-TNF-α therapy showed promising results; however, these were open-label and based on patient-reported outcome measures. In this study, we developed a caninized TNF-α receptor-Fc (caTNFR-Fc) fusion protein and conducted a non-randomized, open-label, pilot study in dogs with OA using objectively measured ground reaction forces and activity. The aims of the study were to assess the efficacy of the intra-articular (IA) injection of the caTNFR-Fc fusion protein as a treatment for OA pain, and additionally to evaluate TNF concentrations in synovial fluid (SF) between joints with/without OA in dogs. Dogs (n = 12) with single-limb lameness due to single joint appendicular OA were recruited. All dogs received caTNFR-Fc fusion protein injection into the affected joint under sedation. Objective kinetic gait analysis using force plate was performed prior to (baseline), and at 14- and 28-days following treatment. Additionally, SF samples were collected from OA joints (n = 69) and non-OA joints (n = 79) in a different cohort of dogs and TNF-α were measured using enzyme-linked immunosorbent assay. No significant treatment effects on the limb use, activity, and the questionnaire were found. The concentration of TNF-α was significantly higher in OA joints than in healthy joints (p = 0.0019), but TNF-α was detected in only 10/69 OA samples. The IA injection of caTNFR-Fc fusion protein provided no benefit in terms of objective limb use and activity data in dogs with OA in this pilot study. Although the SF concentration of TNF-α was significantly higher in OA joints, few OA joints had measurable TNF-α. Collectively, the data indicate TNF-α may not be a good therapeutic target in canine OA.