Neuronal double-stranded DNA accumulation induced by DNase II deficiency drives tau phosphorylation and neurodegeneration.

BACKGROUND: Deoxyribonuclease 2 (DNase II) plays a key role in clearing cytoplasmic double-stranded DNA (dsDNA). Deficiency of DNase II leads to DNA accumulation in the cytoplasm. Persistent dsDNA in neurons is an early pathological hallmark of senescence and neurodegenerative diseases including Alzheimer's disease (AD). However, it is not clear how DNase II and neuronal cytoplasmic dsDNA influence neuropathogenesis. Tau hyperphosphorylation is a key factor for the pathogenesis of AD. The effect of DNase II and neuronal cytoplasmic dsDNA on neuronal tau hyperphosphorylation remains unclarified. METHODS: The levels of neuronal DNase II and dsDNA in WT and Tau-P301S mice of different ages were measured by immunohistochemistry and immunolabeling, and the levels of DNase II in the plasma of AD patients were measured by ELISA. To investigate the impact of DNase II on tauopathy, the levels of phosphorylated tau, phosphokinase, phosphatase, synaptic proteins, gliosis and proinflammatory cytokines in the brains of neuronal DNase II-deficient WT mice, neuronal DNase II-deficient Tau-P301S mice and neuronal DNase II-overexpressing Tau-P301S mice were evaluated by immunolabeling, immunoblotting or ELISA. Cognitive performance was determined using the Morris water maze test, Y-maze test, novel object recognition test and open field test. RESULTS: The levels of DNase II were significantly decreased in the brains and the plasma of AD patients. DNase II also decreased age-dependently in the neurons of WT and Tau-P301S mice, along with increased dsDNA accumulation in the cytoplasm. The DNA accumulation induced by neuronal DNase II deficiency drove tau phosphorylation by upregulating cyclin-dependent-like kinase-5 (CDK5) and calcium/calmodulin activated protein kinase II (CaMKII) and downregulating phosphatase protein phosphatase 2A (PP2A). Moreover, DNase II knockdown induced and significantly exacerbated neuron loss, neuroinflammation and cognitive deficits in WT and Tau-P301S mice, respectively, while overexpression of neuronal DNase II exhibited therapeutic benefits. CONCLUSIONS: DNase II deficiency and cytoplasmic dsDNA accumulation can initiate tau phosphorylation, suggesting DNase II as a potential therapeutic target for tau-associated disorders.

Mouse serum albumin induces neuronal apoptosis and tauopathies.

The elderly frequently present impaired blood-brain barrier which is closely associated with various neurodegenerative diseases. However, how the albumin, the most abundant protein in the plasma, leaking through the disrupted BBB, contributes to the neuropathology remains poorly understood. We here demonstrated that mouse serum albumin-activated microglia induced astrocytes to A1 phenotype to remarkably increase levels of Elovl1, an astrocytic synthase for very long-chain saturated fatty acids, significantly promoting VLSFAs secretion and causing neuronal lippoapoptosis through endoplasmic reticulum stress response pathway. Moreover, MSA-activated microglia triggered remarkable tau phosphorylation at multiple sites through NLRP3 inflammasome pathway. Intracerebroventricular injection of MSA into the brains of C57BL/6J mice to a similar concentration as in patient brains induced neuronal apoptosis, neuroinflammation, increased tau phosphorylation, and decreased the spatial learning and memory abilities, while Elovl1 knockdown significantly prevented the deleterious effect of MSA. Overall, our study here revealed that MSA induced tau phosphorylation and neuron apoptosis based on MSA-activated microglia and astrocytes, respectively, showing the critical roles of MSA in initiating the occurrence of tauopathies and cognitive decline, and providing potential therapeutic targets for MSA-induced neuropathology in multiple neurodegenerative disorders.

Thrombomodulin reduces α-synuclein generation and ameliorates neuropathology in a mouse model of Parkinson's disease.

The neurotoxic α-synuclein (α-syn) oligomers play an important role in the occurrence and development of Parkinson's disease (PD), but the factors affecting α-syn generation and neurotoxicity remain unclear. We here first found that thrombomodulin (TM) significantly decreased in the plasma of PD patients and brains of A53T α-syn mice, and the increased TM in primary neurons reduced α-syn generation by inhibiting transcription factor p-c-jun production through Erk1/2 signaling pathway. Moreover, TM decreased α-syn neurotoxicity by reducing the levels of oxidative stress and inhibiting PAR1-p53-Bax signaling pathway. In contrast, TM downregulation increased the expression and neurotoxicity of α-syn in primary neurons. When TM plasmids were specifically delivered to neurons in the brains of A53T α-syn mice by adeno-associated virus (AAV), TM significantly reduced α-syn expression and deposition, and ameliorated the neuronal apoptosis, oxidative stress, gliosis and motor deficits in the mouse models, whereas TM knockdown exacerbated these neuropathology and motor dysfunction. Our present findings demonstrate that TM plays a neuroprotective role in PD pathology and symptoms, and it could be a novel therapeutic target in efforts to combat PD. Schematic representation of signaling pathways of TM involved in the expression and neurotoxicity of α-syn. A TM decreased RAGE, and resulting in the lowered production of p-Erk1/2 and p-c-Jun, and finally reduce α-syn generation. α-syn oligomers which formed from monomers increase the expression of p-p38, p53, C-caspase9, C-caspase3 and Bax, decrease the level of Bcl-2, cause mitochondrial damage and lead to oxidative stress, thus inducing neuronal apoptosis. TM can reduce intracellular oxidative stress and inhibit p53-Bax signaling by activating APC and PAR-1. B The binding of α-syn oligomers to TLR4 may induce the expression of IL-1ß, which is subsequently secreted into the extracellular space. This secreted IL-1ß then binds to its receptor, prompting p65 to translocate from the cytoplasm into the nucleus. This translocation downregulates the expression of KLF2, ultimately leading to the suppression of TM expression. By Figdraw.

ArhGAP11A mediates amyloid-ß generation and neuropathology in an Alzheimer's disease-like mouse model.

Amyloid-ß (Aß) plays an important role in the neuropathology of Alzheimer's disease (AD), but some factors promoting Aß generation and Aß oligomer (Aßo) neurotoxicity remain unclear. We here find that the levels of ArhGAP11A, a Ras homology GTPase-activating protein, significantly increase in patients with AD and amyloid precursor protein (APP)/presenilin-1 (PS1) mice. Reducing the ArhGAP11A level in neurons not only inhibits Aß generation by decreasing the expression of APP, PS1, and ß-secretase (BACE1) through the RhoA/ROCK/Erk signaling pathway but also reduces Aßo neurotoxicity by decreasing the expressions of apoptosis-related p53 target genes. In APP/PS1 mice, specific reduction of the ArhGAP11A level in neurons significantly reduces Aß production and plaque deposition and ameliorates neuronal damage, neuroinflammation, and cognitive deficits. Moreover, Aßos enhance ArhGAP11A expression in neurons by activating E2F1, which thus forms a deleterious cycle. Our results demonstrate that ArhGAP11A may be involved in AD pathogenesis and that decreasing ArhGAP11A expression may be a promising therapeutic strategy for AD treatment.

Inoculation With Indigenous Rhizosphere Microbes Enhances Aboveground Accumulation of Lead in Salix integra Thunb. by Improving Transport Coefficients.

The application of plant-microbial remediation of heavy metals is restricted by the difficulty of exogenous microbes to form large populations and maintain their long-term remediation efficiency. We therefore investigated the effects of inoculation with indigenous heavy-metal-tolerant rhizosphere microbes on phytoremediation of lead (Pb) by Salix integra. We measured plant physiological indexes and soil Pb bioavailability and conducted widespread targeted metabolome analysis of strains to better understand the mechanisms of enhance Pb accumulation. Growth of Salix integra was improved by both single and co-inoculation treatments with Bacillus sp. and Aspergillus niger, increasing by 14% in co-inoculated plants. Transfer coefficients for Pb, indicating mobility from soil via roots into branches or leaves, were higher following microbial inoculation, showing a more than 100% increase in the co-inoculation treatment over untreated plants. However, Pb accumulation was only enhanced by single inoculation treatments with either Bacillus sp. or Aspergillus niger, being 10% greater in plants inoculated with Bacillus sp. compared with uninoculated controls. Inoculation mainly promoted accumulation of Pb in aboveground plant parts. Superoxide dismutase and catalase enzyme activities as well as the proline content of inoculated plants were enhanced by most treatments. However, soil urease and catalase activities were lower in inoculated plants than controls. Proportions of acid-soluble Pb were 0.34 and 0.41% higher in rhizosphere and bulk soil, respectively, of plants inoculated with Bacillus sp. than in that of uninoculated plants. We identified 410 metabolites from the microbial inoculations, of which more than 50% contributed to heavy metal bioavailability; organic acids, amino acids, and carbohydrates formed the three major metabolite categories. These results suggest that both indigenous Bacillus sp. and Aspergillus niger could be used to assist phytoremediation by enhancing antioxidant defenses of Salix integra and altering Pb bioavailability. We speculate that microbial strains colonized the soil and plants at the same time, with variations in their metabolite profiles reflecting different living conditions. We also need to consider interactions between inocula and the whole microbial community when applying microbial inoculation to promote phytoremediation.

[Soil microorganisms, nutrients and enzyme activity of Larix kaempferi plantation under different ages in mountainous region of eastern Liaoning Province, China].

We studied the community of soil microorganisms, enzyme activity and soil nutrients under 11-, 20-, 34-and 47-year-old Larix kaempferi plantations in mountainous region of eastern Liaoning Province to discuss the soil biological properties of L. kaempferi plantations of different stand ages and their relationships with soil nutrients. The results showed that the indexes reflecting soil micro-organisms, enzyme activity and soil nutrients of L. kaempferi plantations were the highest under the 11- or 47-year-old stand and the lowest in the 20- or 34-year-old stand. Soil productivity appeared in a decline trend with the increasing stand age, and the changes of soil microbial community structure and enzyme activity were responsive to soil degradation. The difference of fungi community was more noticeable than that of bacteria community among the plantations with different stand ages. The results of CCA showed soil nutrient and pH had no effect on seasonal difference of community structure, but had effects on community, structure among different stand ages. The total N, organic carbon, C/N, available nitrogen, exchangeable Mg2+ and pH had greater effects on bacteria community, while available P, total K and pH had greater effect on fungi community among different age forests. The main T-RFs of bacteria and fungi had higher correlation with N and P, and the fungi community had higher correlation with organic carbon and K than bacteria community. The microor-ganism community of the 11- and 47-year-old stands had greater correlation with soil nutrients and enzyme activity than that of 20- and 34-year-old stands. Consequently, soil organisms, in particular soil fungi, could be used to indicate soil degradation.