We are honored to invite Prof. Xiao-Jiang Li as our journal's Guest Editor to recognize a special issue "Animal Models of Different Species for Investigating Neurodegenerative Diseases".
This week, we've collected the latest articles in the field of animal models and neurodegenerative diseases combined with this hot topic. Welcome your all to read and share articles, and follow AND journals.
Title: Genetically engineered pig models of neurological diseases
Authors: Caijuan Li, Jun Li, Liangxue Lai, Shihua Li, Sen Yan
Genetically modified animal models are commonly used for in vivo studies of human diseases. Mice are the most common animal models used in biomedical research, which have provided important insights into disease pathogenesis and are widely used to find treatments for diseases. However, due to the differences in the anatomical structure and physiological function between human and mouse brains, most genetically modified mouse models cannot fully recapitulate the overt and selective neuronal loss seen in age-dependent neurodegeneration diseases. While non-human primates (NHP) are closer to humans and have been used to model human disease, these models are difficult to be utilized at a large scale due to various limitations including their high costs, prolonged breeding time, community concerns for use of NHP, and high ethical standards. As an important animal resource in agriculture, pigs are also used as animal models in biomedical research. The central nervous system of pigs is highly similar to that of humans, making pig models suitable for investigating neurological diseases. The relatively short breeding period, large litter size, and established somatic cell transfer technology are advantages over NHP for using pigs to model human diseases. The recent development of gene editing tools allows one to more efficiently generate pig models that can precisely mimic genetic mutations in neurological diseases. In this review, we summarize recent advances in the use of pigs for modeling human neurological diseases, including new approaches for generating genetically modified pig models.
Access this article: http://dx.doi.org/10.20517/and.2022.13
Title: Modeling neurodegenerative diseases using non-human primates: advances and challenges
Authors: Bang Li, Da-Jian He, Xiao-Jiang Li, Xiang-Yu Guo
Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are pathologically characterized by progressive loss of selective populations of neurons in the affected brain regions and clinically manifested by cognitive, motor, and psychological dysfunctions. Since aging is the major risk factor for NDs and the elderly population is expected to expand considerably in the coming decades, the prevalence of NDs will significantly increase, leading to a greater medical burden to society and affected families. Despite extensive research on NDs, no effective therapy is available for NDs, largely due to a lack of complete understanding of the pathogenesis of NDs. Although research on small animal and rodent models has provided tremendous knowledge of molecular mechanisms of disease pathogenesis, few translational successes have been reported in clinical trials. In particular, most genetically modified rodent models are unable to recapitulate striking and overt neurodegeneration seen in the patient brains. Non-human primates (NHPs) are the most relevant laboratory animals to humans, and recent studies using NHP neurodegeneration models have uncovered important pathological features of NDs. Here, we review the unique features of NHPs for modeling NDs and new insights into AD, PD, and ALS gained from animal models, highlight the contribution of gene editing techniques to establishing NHP models, and discuss the challenges of investigating NHP models.
Access this article: http://dx.doi.org/10.20517/and.2022.14
Title: Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of Aβ1-42 Mice via α7nAChR-Dependent BDNF Upregulation
Authors: Chengyun Cai, Lifeng Wang, Shixin Li, Shengchun Lou, Jia-lie Luo, Ding-Yi Fu and Tingting Chen
Type: Research Article
Alzheimer's disease (AD) is characterized pathologically by the structural and functional impairments of synapses in the hippocampus, inducing the learning and memory deficiencies. Ras GTPase is closely related to the synaptic function and memory. This study was to investigate the effects of farnesyl transferase inhibitor lonafarnib on the synaptic structure and function in AD male mice and explore the potential mechanism. Our results showed 50 mg/kg lonafarnib (intraperitoneal) rescued the impaired spatial memory and improved the damaged synaptic transmission and plasticity of Aβ1-42 mice. In addition, lonafarnib ameliorated the morphology of synaptic dendrites and spines in Aβ1-42 mice. Furthermore, lonafarnib enhanced α7nAChR cell surface expression and phosphorylation of downstream Akt and CaMKII in Aβ1-42 mice, which were inhibited by α7nAChR antagonist methyl lycaconitine (MLA), and increased the phosphorylation of CREB in a CaMKII- but not ERK-dependent way. Lonafarnib enhanced hippocampal brain-derived neurotrophic factor (BDNF) concentration in Aβ1-42 mice, which was sensitive to MLA and KN93 (an inhibitor of CaMKII), but not related to ERK and Akt pathways. H-Ras, but not Rhes, was related to the lonafarnib induced improvement of α7nAChR cell surface expression and BDNF content. Interestingly, lonafarnib induced improvement of synaptic transmission, plasticity and spatial cognition in Aβ1-42 mice was abolished by BDNF deprivation with TrkB/Fc chimera protein. Our results indicate that lonafarnib can rescue the structural and functional impairments of synapses in the Aβ1-42 mice, which may be related to the improvement of BDNF content through the H-Ras-α7nAChR-dependent CaMKII-CREB pathway, leading to the improvement of spatial cognition.
Access this article: https://doi.org/10.1523/JNEUROSCI.1989-21.2022
Title: Activation of locus coeruleus-spinal cord noradrenergic neurons alleviates neuropathic pain in mice via reducing neuroinflammation from astrocytes and microglia in spinal dorsal horn
Authors: Juan Li, Yiyong Wei, Junli Zhou, Helin Zou, Lulin Ma, Chengxi Liu, Zhi Xiao, Xingfeng Liu, Xinran Tan, Tian Yu, Song Cao
Type: Research Article
Background: The noradrenergic neurons of locus coeruleus (LC) project to the spinal dorsal horn (SDH), and release norepinephrine (NE) to inhibit pain transmission. However, its effect on pathological pain and the cellular mechanism in the SDH remains unclear. This study aimed to explore the analgesic effects and the anti-neuroinflammation mechanism of LC-spinal cord noradrenergic pathway (LC:SC) in neuropathic pain (NP) mice with sciatic chronic constriction injury.
Methods: The Designer Receptors Exclusively Activated by Designer Drugs (DREADD) was used to selectively activate LC:SC. Noradrenergic neuron-specific retro-adeno-associated virus was injected to the spinal cord. Pain threshold, LC and wide dynamic range (WDR) neuron firing, neuroinflammation (microglia and astrocyte activation, cytokine expression), and α2AR expression in SDH were evaluated.
Results: Activation of LC:SC with DREADD increased the mechanical and thermal nociceptive thresholds and reduced the WDR neuron firing. LC:SC activation (daily, 7 days) downregulated TNF-α and IL-1β expression, upregulated IL-4 and IL-10 expression in SDH, and inhibited microglia and astrocytes activation in NP mice. Immunofluorescence double staining confirmed that LC:SC activation decreased the expression of cytokines in microglia of the SDH. In addition, the effects of LC:SC activation could be reversed by intrathecal injection of yohimbine. Immunofluorescence of SDH showed that NE receptor α2B-AR was highly expressed in microglia in CCI mice.
Conclusion: These findings indicate that selective activation of LC:SC alleviates NP in mice by increasing the release of NE and reducing neuroinflammation of astrocytes and microglia in SDH.
Access this article: https://doi.org/10.1186/s12974-022-02489-9
Title: Targeting thalamic circuits rescues motor and mood deficits in PD mice
Authors: Ying Zhang, Dheeraj S Roy, Yi Zhu, Yefei Chen, Tomomi Aida, Yuanyuan Hou, Chenjie Shen, Nicholas E Lea, Margaret E Schroeder, Keith M Skaggs, Heather A Sullivan, Kyle B Fischer, Edward M Callaway, Ian R Wickersham, Ji Dai, Xiao-Ming Li, Zhonghua Lu, Guoping Feng
Type: Research Article
Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.
Access this article: https://doi.org/10.1038/s41586-022-04806-x