Rutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer's disease.

BACKGROUND: Tau pathology is a hallmark of Alzheimer's disease (AD) and other tauopathies. During disease progression, abnormally phosphorylated forms of tau aggregate and accumulate into neurofibrillary tangles, leading to synapse loss, neuroinflammation, and neurodegeneration. Thus, targeting of tau pathology is expected to be a promising strategy for AD treatment. METHODS: The effect of rutin on tau aggregation was detected by thioflavin T fluorescence and transmission electron microscope imaging. The effect of rutin on tau oligomer-induced cytotoxicity was assessed by MTT assay. The effect of rutin on tau oligomer-mediated the production of IL-1ß and TNF-α in vitro was measured by ELISA. The uptake of extracellular tau by microglia was determined by immunocytochemistry. Six-month-old male Tau-P301S mice were treated with rutin or vehicle by oral administration daily for 30 days. The cognitive performance was determined using the Morris water maze test, Y-maze test, and novel object recognition test. The levels of pathological tau, gliosis, NF-kB activation, proinflammatory cytokines such as IL-1ß and TNF-α, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunolabeling, immunoblotting, or ELISA. RESULTS: We showed that rutin, a natural flavonoid glycoside, inhibited tau aggregation and tau oligomer-induced cytotoxicity, lowered the production of proinflammatory cytokines, protected neuronal morphology from toxic tau oligomers, and promoted microglial uptake of extracellular tau oligomers in vitro. When applied to Tau-P301S mouse model of tauopathy, rutin reduced pathological tau levels, regulated tau hyperphosphorylation by increasing PP2A level, suppressed gliosis and neuroinflammation by downregulating NF-kB pathway, prevented microglial synapse engulfment, and rescued synapse loss in mouse brains, resulting in a significant improvement of cognition. CONCLUSION: In combination with the previously reported therapeutic effects of rutin on Aß pathology, rutin is a promising drug candidate for AD treatment based its combinatorial targeting of tau and Aß.

Resveratrol Rescues Tau-Induced Cognitive Deficits and Neuropathology in a Mouse Model of Tauopathy.

BACKGROUND: Alzheimer's Disease (AD) is characterized by the presence of extracellular amyloid-ß (Aß) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aß generation and Aß-induced neurocytotoxicity, while its effect on tau pathology is still unknown. METHODS: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1ß, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. RESULTS: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. CONCLUSION: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

An oligomer-specific antibody improved motor function and attenuated neuropathology in the SOD1-G93A transgenic mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease characterized by motor neuron loss in the brain and spinal cord. Mutations in Cu-Zn superoxide dismutase (SOD1) are the first identified genetic mutations that are causative for familial ALS. Soluble SOD1 oligomers are considered the most toxic species and play a key role in the pathologic process of ALS. Here we present a therapeutic strategy for ALS with an oligomer-specific antibody (W20) targeting toxic SOD1 oligomers. Our study showed that W20 significantly improved motor neuron survival and motor performance in SOD1-G93A mouse model of ALS when administrated even at low dose within short time. Further investigation demonstrated that the beneficial effects of W20 resulted from the reduction of SOD1 oligomer levels and the inhibition of gliosis and neuroinflammation in the spinal cords and brain stems of ALS model mice. These findings for the first time suggest that an oligomer-specific antibody has promising therapeutic potential for ALS and open a new way for ALS treatment.

Intravenous immunoglobulin ameliorates motor and cognitive deficits and neuropathology in R6/2 mouse model of Huntington's disease by decreasing mutant huntingtin protein level and normalizing NF-κB signaling pathway.

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive movement disorders and cognitive deficits, which is caused by a CAG-repeat expansion encoding an extended polyglutamine (polyQ) tract in the huntingtin protein (HTT). Reduction of mutant HTT levels and inhibition of neuroinflammation has been proposed as a major therapeutic strategy in treating HD. Intravenous immunoglobulin (IVIg) therapy has been firmly established for the treatment of several autoimmune or inflammatory neurological diseases, either as adjunctive treatment or as first-line therapy. However, whether IVIg has therapeutic potential on HD remains unclear. Here we for the first time demonstrated that IVIg treatment remarkably rescued motor and cognitive deficits, prevented synaptic degeneration, attenuated neuroinflammation and oxidative stress in R6/2 mouse model. Further investigation showed that the beneficial effects of IVIg resulted from the reduced levels of mutant HTT and inhibition of NF-κB signalling pathway. These findings suggest that IVIg is a promising therapeutic potential for HD.

Intravenous immunoglobulin improves glucose control and ß-cell function in human IAPP transgenic mice by attenuating islet inflammation and reducing IAPP oligomers.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by ß-cell loss, insulin resistance, islet inflammation and amyloid deposits derived from islet amyloid polypeptide (IAPP). Reducing toxic IAPP oligomers and inhibiting islet inflammation may provide therapeutic benefit in treating T2DM. Intravenous immunoglobulin (IVIg) is an efficient anti-inflammatory and immunomodulatory agent for the treatment of several autoimmune or inflammatory neurological diseases. However, whether IVIg has therapeutic potential on T2DM remains unclear. In present study, we showed that IVIg treatment significantly improved glucose control and insulin sensitivity, and prevented ß-cell apoptosis by lowering toxic IAPP oligomer levels, attenuating islet inflammation and activating autophagy in human IAPP transgenic mouse model. These results suggest that IVIg is a promising therapeutic potential for T2DM treatment.

A vaccine with Aß oligomer-specific mimotope attenuates cognitive deficits and brain pathologies in transgenic mice with Alzheimer's disease.

BACKGROUND: ß-Amyloid peptide (Aß) oligomers are initial factors used to induce Alzheimer's disease (AD) development, and Aß monomers have normal physiological function. The antibodies or vaccines against Aß monomers have serious problems, such as side effects and low curative effects. Therefore, it is essential to specifically target Aß oligomers rather than monomers for the treatment of AD. METHODS: The mimotopes of Aß oligomers were obtained by panning the phage-displayed random peptide libraries using oligomer-specific antibodies as targets and expressed on the surface of EBY100 Saccharomyces cerevisiae to generate yeast cell base vaccines. One vaccine (AOE1) induced antibodies specifically against Aß oligomers and was selected for further study. The APP/PS1 mice were subcutaneously immunized with AOE1 eight times. The levels and characteristics of antibodies induced by AOE1 were determined by enzyme-linked immunosorbent assay. The effect of AOE1 on the cognitive deficits of AD mice was tested by novel object recognition (NOR) and Y-maze. Dot blot analysis, Western blot analysis, and immunohistochemistry were applied to measure the effects of AOE1 on Aß pathologies, neuroinflammation, and microhemorrhages in the brains of AD mice. RESULTS: Eight mimotope candidates of Aß oligomers were selected and expressed on EBY100 S. cerevisiae. Only AOE1 vaccine containing mimotope L2 induced antibodies that specifically recognized Aß42 oligomers rather than monomers. AOE1 immunization significantly increased the AD mice's exploration times for the novel object in the NOR test and the choices for new arms in the Y-maze test, and it reduced levels of Aß oligomers and glial activation in the AD mouse brains. No activation of Aß-specific T cells and microhemorrhages was observed in their brains following AOE1 vaccination. CONCLUSIONS: AOE1 is the first vaccine applying the oligomer-specific mimotope as an immunogen, which could induce antibodies with high specificity to Aß oligomers. AOE1 immunization attenuated Aß pathologies and cognitive deficits in AD mice, decreased the overactivation of glial cells, and did not induce microhemorrhage in the brains of AD mice. These findings suggest that AOE1 may be a safer and more effective vaccine for AD treatment.