Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

BACKGROUND: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. METHODS: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. RESULT: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. CONCLUSION: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

SIRT3 ameliorates diabetes-associated cognitive dysfunction via regulating mitochondria-associated ER membranes.

BACKGROUND: Diabetes is associated with an increased risk of cognitive decline and dementia. These diseases are linked with mitochondrial dysfunction, most likely as a consequence of excessive formation of mitochondria-associated membranes (MAMs). Sirtuin3 (SIRT3), a key mitochondrial NAD+-dependent deacetylase, is critical responsible for mitochondrial functional homeostasis and is highly associated with neuropathology. However, the role of SIRT3 in regulating MAM coupling remains unknown. METHODS: Streptozotocin-injected diabetic mice and high glucose-treated SH-SY5Y cells were established as the animal and cellular models, respectively. SIRT3 expression was up-regulated in vivo using an adeno-associated virus in mouse hippocampus and in vitro using a recombinant lentivirus vector. Cognitive function was evaluated using behavioural tests. Hippocampus injury was assessed using Golgi and Nissl staining. Apoptosis was analysed using western blotting and TUNEL assay. Mitochondrial function was detected using flow cytometry and confocal fluorescence microscopy. The mechanisms were investigated using co-immunoprecipitation of VDAC1-GRP75-IP3R complex, fluorescence imaging of ER and mitochondrial co-localisation and transmission electron microscopy of structural analysis of MAMs. RESULTS: Our results demonstrated that SIRT3 expression was significantly reduced in high glucose-treated SH-SY5Y cells and hippocampal tissues from diabetic mice. Further, up-regulating SIRT3 alleviated hippocampus injuries and cognitive impairment in diabetic mice and mitigated mitochondrial Ca2+ overload-induced mitochondrial dysfunction and apoptosis. Mechanistically, MAM formation was enhanced under high glucose conditions, which was reversed by genetic up-regulation of SIRT3 via reduced interaction of the VDAC1-GRP75-IP3R complex in vitro and in vivo. Furthermore, we investigated the therapeutic effects of pharmacological activation of SIRT3 in diabetic mice via honokiol treatment, which exhibited similar effects to our genetic interventions. CONCLUSIONS: In summary, our findings suggest that SIRT3 ameliorates cognitive impairment in diabetic mice by limiting aberrant MAM formation. Furthermore, targeting the activation of SIRT3 by honokiol provides a promising therapeutic candidate for diabetes-associated cognitive dysfunction. Overall, our study suggests a novel role of SIRT3 in regulating MAM coupling and indicates that SIRT3-targeted therapies are promising for diabetic dementia patients.

Clemastine fumarate attenuates tauopathy and meliorates cognition in hTau mice via autophagy enhancement.

Clemastine fumarate, which has been identified as a promising agent for remyelination and autophagy enhancement, has been shown to mitigate Aß deposition and improve cognitive function in the APP/PS1 mouse model of Alzheimer's disease. Based on these findings, we investigated the effect of clemastine fumarate in hTau mice, a different Alzheimer's disease model characterized by overexpression of human Tau protein. Surprisingly, clemastine fumarate was effective in reducing pathological deposition of Tau protein, protecting neurons and synapses from damage, inhibiting neuroinflammation, and improving cognitive impairment in hTau mice. Interestingly, chloroquine, an autophagy inhibitor, had a significant impact on total and Sarkosyl fractions of autophagy, demonstrating that it can interrupt autophagy. Notably, after administration of chloroquine, levels of Tau protein were significantly increased. When clemastine fumarate was co-administered with chloroquine, the protective effects were reversed, indicating that clemastine fumarate indeed triggered autophagy and promoted the degradation of Tau protein, while also inhibiting further Tauopathy-related neuroinflammation and synapse loss to improve cognitive function in hTau mice.

A Flexible Multi-Channel Hollow CNT/Carbon Nanofiber Composites with S/N Co-Doping for Sodium/Potassium Ion Energy Storage.

Carbon fibrous materials are the promising candidate for the anode of flexible sodium-ion batteries and potassium-ion batteries due to the structural advantages. However, the progress of mechanically robust anode materials with high electrochemical properties is still unsatisfactory for the flexible electrodes. Herein, the comprehensive design of the morphology with unique multi-channel hollow 1D/1D carbon nanotube/carbon nanofiber network and the lattice structure of carbon with S/N co-doping has been proposed. Benefiting from the enlarged interlayer spacing and the flexible fibrous network, the S/N doped carbon nanotube/carbon nanofiber composites (CNT/SNCF) possess not only high conductivity but also good structural stability during sodiation and potassiation processes. When used as anode materials in SIBs and PIBs, the free-standing CNT/SNCF electrodes exhibit high discharge capacities (274.1 and 212.5 mA h g-1 at 1 A/g after 1000 cycles, respectively), superior cycle stability (150.4 and 100.1 mA h g-1 at 5 A/g after 5000 cycles, respectively) and rate performance (109.3 mA h g-1 at 10 A/g and 108.7 mA h g-1 at 5 A/g, respectively), showing great prospects in flexible energy storage devices.

Plasma-Introduced Oxygen Defects Confined in Li4Ti5O12 Nanosheets for Boosting Lithium-Ion Diffusion.

Although Li4Ti5O12 (LTO) is considered as a promising anode material for high-power Li-ion batteries with high safety, the sluggish Li-ion diffusion coefficient restricts its widespread application. In this work, oxygen vacancy was successfully incorporated into LTO by an eco-friendly and cost-effective plasma process. The deficient LTO delivers much higher capacities of 173.4 mAh g-1 at 1C rate after 100 cycles and 140.5 mAh g-1 at 5C after 1000 cycles than those of pristine LTO. Meanwhile, even at a high rate of 20C, it displays an ultrahigh capacity of 133.1 mAh g-1 after 500 cycles with a Coulombic efficiency of 100%. Detailed analysis reveals that the lithium storage mechanisms in the oxygen-deficient LTO, especially at high rate, were dominated by the insertion behavior and dual-phase conversion due to the fast ion-diffusion ability, rather than the widely reported surface capacitance by other approaches. This work highlights that defect generation by plasma in nanomaterials is an effective way to promote ion mobility, especially at high rates, and thus can be extended to other electrode materials for advanced energy-storage applications.