SARS-CoV-2 remains a global health crisis even with effective vaccines and the availability of FDA approved therapies. Efforts to understand the complex disease pathology and develop effective strategies to limit mortality and morbidity are needed. Recent studies reveal circulating Galectin-9 (gal-9), a soluble beta-galactoside binding lectin with immunoregulatory properties, are elevated in SARS-CoV-2 infected individuals with moderate to severe disease. Moreover, in silico studies demonstrate gal-9 can potentially competitively bind the ACE2 receptor on susceptible host cells. Here, we determined whether early introduction of exogenous gal-9 following SARS-CoV-2 infection in humanized ACE2 transgenic mice (K18-hACE2) may reduce disease severity. Mice were infected and treated with a single dose of a human recombinant form of gal-9 (rh-gal-9) and monitored for morbidity. Subgroups of mice were humanely euthanized at 2- and 5- days post infection (dpi) for viral levels by plaque assay, immune changes measures by flow cytometry, and soluble mediators by protein analysis from lung tissue and bronchoalveolar Lavage fluid (BALF). Mice treated with rh-gal-9 during acute infection had improved survival compared to PBS treated controls. At 5 dpi, rh-gal-9 treated mice had enhanced viral clearance in the BALF, but not in the lung parenchyma. Increased T and dendritic cells and decreased neutrophil frequencies in the lung at 5 dpi were observed, whereas BALF had elevated levels of type-I interferons and proinflammatory cytokines. These results suggest a role for rh-gal-9 in limiting acute COVID-19. Further studies are required to determine the optimal design of gal-9 treatment to effectively ameliorate COVID-19 disease.

Objective

Ehlers-Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers-Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative.

Case report

A 27-year-old Caucasian female with a history of Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7-8 out of 10 to 0-3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs.

Conclusion

Ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers-Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.

The authors regret an error involving the order of authorship that was missed during the final submission process of our manuscriptrecently published in the Journal Brain Research Bulletin.The updated author list is mentioned above.The authors would like to apologise for any inconvenience caused.

Alzheimer's disease is a neurodegenerative disease associated with progressive memory and cognitive decline. Previous studies have identified the benefits of cognitive enrichment on reducing disease pathology. Additionally, epidemiological and clinical data suggest that repeated exercise, and cognitive and social enrichment, can improve and/or delay the cognitive deficiencies associated with aging and neurodegenerative diseases. In the present study, 3xTg-AD mice were exposed to a rigorous training routine beginning at 3 months of age, which consisted of repeated training in the Morris water maze spatial recognition task every 3 months, ending at 18 months of age. At the conclusion of the final Morris water maze training session, animals subsequently underwent testing in another hippocampus-dependent spatial task, the Barnes maze task, and on the more cortical-dependent novel object recognition memory task. Our data show that periodic cognitive enrichment throughout aging, via multiple learning episodes in the Morris water maze task, can improve the memory performance of aged 3xTg-AD mice in a separate spatial recognition task, and in a preference memory task, when compared to naive aged matched 3xTg-AD mice. Furthermore, we observed that the cognitive enrichment properties of Morris water maze exposer, was detectable in repeatedly trained animals as early as 6 months of age. These findings suggest early repeated cognitive enrichment can mitigate the diverse cognitive deficits observed in Alzheimer's disease.

Transplantation of neural stem cells (NSCs) can improve cognition in animal models of Alzheimer's disease (AD). However, AD is a protracted disorder, and prior studies have examined only short-term effects. We therefore used an immune-deficient model of AD (Rag-5xfAD mice) to examine long-term transplantation of human NSCs (StemCells Inc.; HuCNS-SCs). Five months after transplantation, HuCNS-SCs had engrafted and migrated throughout the hippocampus and exhibited no differences in survival or migration in response to β-amyloid pathology. Despite robust engraftment, HuCNS-SCs failed to terminally differentiate and over a quarter of the animals exhibited ectopic human cell clusters within the lateral ventricle. Unlike prior short-term experiments with research-grade HuCNS-SCs, we also found no evidence of improved cognition, no changes in brain-derived neurotrophic factor, and no increase in synaptic density. These data, while disappointing, reinforce the notion that individual human NSC lines need to be carefully assessed for efficacy and safety in appropriate long-term models.

Alzheimer disease is characterized by the accumulation of β-amyloid (Aβ) plaques and tau-laden neurofibrillary tangles. Emerging studies suggest that in neurodegenerative diseases, aggregation of one protein species can promote other proteinopathies and that inflammation plays an important role in this process. To study the interplay between Aβ deposition, tau pathology, and microgliosis, we established a new AD transgenic mouse model by crossing 5xfAD mice with Thy-Tau22 transgenic mice. The resulting 'T5x' mice exhibit a greater than three-fold increase in misfolded and hyperphosphorylated tau and further substantiates the hypothesis that Aβ accelerates tau pathology. Surprisingly, T5x mice exhibit a 40-50 % reduction in Aβ plaque load and insoluble Aβ species when compared with aged-matched 5xfAD littermates. T5x mice exhibit significant changes in cytokine production, an almost doubling of microglial number, and a dramatic shift in microglia activation state. Furthermore, T5x microglia exhibit increased phagocytic capacity that enhances the clearance of insoluble Aβ and decreasing plaque load. Therefore, our results suggest that strategies to increase the phagocytic ability of microglia can be employed to reduce Aβ and that tau-induced changes in microglial activation state can promote the clearance of Aβ.

Abstract Background Age-related neurodegenerative diseases share a number of important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates. Results We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunological analysis of a number of different prefibrillar Aβ oligomer preparations show that structural polymorphisms exist in Aβ prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot analysis demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of Aβ prefibrillar oligomers can serve as they serve as templates for monomer addition, indicating that they seed the conversion of Aβ monomer into more prefibrillar oligomers of the same type. Conclusions These results indicate that distinct structural variants or conformers of prefibrillar Aβ oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.

Background: Age-related neurodegenerative diseases share a number of important pathological features, such as accumulation of misfolded proteins as amyloid oligomers and fibrils. Recent evidence suggests that soluble amyloid oligomers and not the insoluble amyloid fibrils may represent the primary pathological species of protein aggregates. Results: We have produced several monoclonal antibodies that specifically recognize prefibrillar oligomers and do not recognize amyloid fibrils, monomer or natively folded proteins. Like the polyclonal antisera, the individual monoclonals recognize generic epitopes that do not depend on a specific linear amino acid sequence, but they display distinct preferences for different subsets of prefibrillar oligomers. Immunological analysis of a number of different prefibrillar A beta oligomer preparations show that structural polymorphisms exist in A beta prefibrillar oligomers that can be distinguished on the basis of their reactivity with monoclonal antibodies. Western blot analysis demonstrates that the conformers defined by the monoclonal antibodies have distinct size distributions, indicating that oligomer structure varies with size. The different conformational types of A beta prefibrillar oligomers can serve as they serve as templates for monomer addition, indicating that they seed the conversion of A beta monomer into more prefibrillar oligomers of the same type. Conclusions: These results indicate that distinct structural variants or conformers of prefibrillar A beta oligomers exist that are capable of seeding their own replication. These conformers may be analogous to different strains of prions.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has caused a global economic and health crisis. Recently, plasma levels of galectin-9 (Gal-9), a β-galactoside-binding lectin involved in immune regulation and viral immunopathogenesis, were reported to be elevated in the setting of severe COVID-19 disease. However, the impact of Gal-9 on SARS-CoV-2 infection and immunopathology remained to be elucidated. In this study, we demonstrate that Gal-9 treatment potently enhances SARS-CoV-2 replication in human airway epithelial cells (AECs), including immortalized AECs and primary AECs cultured at the air-liquid interface. Gal-9-glycan interactions promote SARS-CoV-2 attachment and entry into AECs in an angiotensin-converting enzyme 2 (ACE2)-dependent manner, enhancing the binding of the viral spike protein to ACE2. Transcriptomic analysis revealed that Gal-9 and SARS-CoV-2 infection synergistically induced the expression of key pro-inflammatory programs in AECs, including the IL-6, IL-8, IL-17, EIF2, and TNFα signaling pathways. Our findings suggest that manipulation of Gal-9 should be explored as a therapeutic strategy for SARS-CoV-2 infection.