Tauopathy promotes spinal cord-dependent production of toxic amyloid-beta in transgenic monkeys.

Tauopathy, characterized by the hyperphosphorylation and accumulation of the microtubule-associated protein tau, and the accumulation of Aß oligomers, constitute the major pathological hallmarks of Alzheimer's disease. However, the relationship and causal roles of these two pathological changes in neurodegeneration remain to be defined, even though they occur together or independently in several neurodegenerative diseases associated with cognitive and movement impairment. While it is widely accepted that Aß accumulation leads to tauopathy in the late stages of the disease, it is still unknown whether tauopathy influences the formation of toxic Aß oligomers. To address this, we generated transgenic cynomolgus monkey models expressing Tau (P301L) through lentiviral infection of monkey embryos. These monkeys developed age-dependent neurodegeneration and motor dysfunction. Additionally, we performed a stereotaxic injection of adult monkey and mouse brains to express Tau (P301L) via AAV9 infection. Importantly, we found that tauopathy resulting from embryonic transgenic Tau expression or stereotaxic brain injection of AAV-Tau selectively promoted the generation of Aß oligomers in the monkey spinal cord. These Aß oligomers were recognized by several antibodies to Aß1-42 and contributed to neurodegeneration. However, the generation of Aß oligomers was not observed in other brain regions of Tau transgenic monkeys or in the brains of mice injected with AAV9-Tau (P301L), suggesting that the generation of Aß oligomers is species- and brain region-dependent. Our findings demonstrate for the first time that tauopathy can trigger Aß pathology in the primate spinal cord and provide new insight into the pathogenesis and treatment of tauopathy.

Generation of inactivated IL2RG and RAG1 monkeys with severe combined immunodeficiency using base editing.

Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.

Evaluation of changes in the cognitive function of adult cynomolgus monkeys under stress induced by audio-visual stimulation by applying modified finger maze test.

Stress in life is ubiquitous and unavoidable. Prolonged exposure to severe stress can lead to physical intolerance and impair cognitive function. Non-human primates are considered to be the best animal model for studying cognitive function, especially memory and attention. The finger maze test, with the advantages of short training time and lower cost, is recommended to evaluate learning and memory in non-human primates. In this study, we modified the finger maze test method to evaluate the cognitive function of single-housed cynomolgus monkeys. The flexibility and attention of cynomolgus monkeys were assessed by performing the complex task test and the stranger intrusion interference test, respectively, which increased the difficulty of obtaining rewards, and the ability of long-term memory was also evaluated by the memory test. Furthermore, the changes in cognitive function of the cynomolgus monkeys were tested by using the finger maze test after audio-visual stimulation, and the changes in the cortisol levels during stimulation were also analyzed. We found that, after completing the learning test, there was no significant decrease in their success rate when monkeys processed multitasks at the same time. In the stranger intrusion interference test, all subjects were distracted, but the accuracy did not decrease. The monkeys completed the memory tests in the 1st and 2nd months after the learning tests, with a high success rate. However, the success rate decreased significantly at the end of the 4th month. During audio-visual stimulation, the plasma cortisol level significantly increased in the first 2 months and was maintained at a high level thereafter. One month after audio-visual stimulation, the accuracy of the memory test was significantly reduced, and the total time of distraction was significantly prolonged. In conclusion, chronic audio-visual stimulation can increase blood cortisol levels and impair cognitive function. The modified finger maze test can evaluate many aspects of cognitive function and assess the changes in the cognitive function of adult cynomolgus monkeys under stress.

Growth and Development Responses of the Rhizome-Root System in Pleioblastus pygmaeus to Light Intensity.

Light, as a primary source of energy, directly or indirectly influences virtually all morphological modifications occurring in both shoots and roots. A pot experiment was conducted to assess the growth patterns of one-year-old Pleioblastus pygmaeus plants' rhizome-root systems and their responses to different light intensities from 11 March to 26 December 2016. The experiment design scheme was 3.87% (L1), 11.25% (L2), 20.25% (L3), 38.76% (L4), 60.70% (L5), and 100% full sunlight (control CK). The results indicated that along the growing period from March to December, eight of the eleven studied parameters of the rhizome-root system showed significant variability and diverse growth patterns. In addition, light intensity is a key factor for determining P. pygmaeus plants' rhizome and root growth. Specifically, the light intensity had a significant, positive, and linear/or almost linear impact on the number of old and new rhizomes, old rhizome length, new rhizome diameter, as well as the culm root diameter. A nonlinear and positive relationship was found between light intensity and the listed three parameters, i.e., new rhizome length, new rhizome internode length, and rhizome root length. The value of the above-mentioned three parameters significantly increased when affected from 0% to 40-60% of full sunlight and then gradually increased until 100% of full sunlight. The ratio of aboveground dry weight to underground dry weight (A/U ratio) showed a single peak curve with increasing light intensity and presented the highest value under ca. 55% full sunlight. Furthermore, 40% full sunlight (equal to an average light of 2232 lux) might be the threshold for P. pygmaeus rhizome-root system growth. When the light intensity was below 40%, the generalized additive models (GAMs) predicted value of most studied parameters decreased to lower than zero. In conclusion, current study provides a solid basis for understanding the dynamic growth and development of P. pygmaeus rhizome-root system, and its responses to different light conditions, which could be used as inputs to P. pygmaeus plant cultivation.

Clinical Application Value of Lactobacillus Plantarum PS128 in Patients with Anxiety Disorders.

Objective: PS128 is a novel psycho biotic strain, it has been reported to play an important role in neuropsychiatric disorders. This study investigated the clinical effect of PS128 supplementation on patients with anxiety. Methods: A total of 200 patients with anxiety were recruited, and divided into two groups (n = 100/group). The control group received oral treatment with citalopram, and the PS128 group received PS128 capsules based on citalopram treatment. Hamilton Anxiety Scale (HAMA) and Self-Rating Anxiety Scale (SAS) were used to evaluate the anxiety levels. After 2 months of continuous administration, clinical efficacy was evaluated according to HAMA score. Results: There was no significant difference in HAMA and SAS scores between the two groups before treatment. With the treatment prolonged, the HAMA and SAS score decreased gradually in both control and PS128 groups, and the decrease rate of PS128 group was significantly greater than that of the control group. The clinical effective rates of PS128 group were higher than those in the control group, high levels of clinical cure rate were also detected in the PS128 group. Compared with the control group (22%), the incidence of adverse reactions was significantly reduced for patients in the PS128 group (4%). Conclusion: The treatment effect of citalopram combined with PS128 against anxiety is satisfactory clinically. It can greatly improve the anxiety symptoms of patients, increase the cure rate, reduce adverse reactions.