Analysis of the effects of a novel anti-inflammatory on anxiety, apathy, and cognition in a mouse model of Alzheimer’s Disease

Alzheimer’s Disease (AD) is the most common form of dementia. It is a fatal neurodegenerative disease that leads to both cognitive decline and altered psychological states. There is currently no cure for AD. The pathology of AD includes the clustering of insoluble amyloid-β (Aβ) plaques, tau tangles, and increased neuroinflammation. These pathological manifestations initially occur in the hippocampus (HPC), then continue to the prefrontal cortex (PFC), and occur throughout the brain as the disease progresses. The heightened neuroinflammatory state in AD is an essential point of focus in AD research. In this study, the novel oral anti-inflammatory tumor necrosis factor-α (TNF-α) inhibitor compound PD2244 was tested to observe its effects on sensorimotor gating using prepulse inhibition (PPI), spatial memory using Barnes Maze, anxiety using an elevated-T maze, and apathy by observing nest building behavior in both female and male 3xTg mice. The 3xTg mice are the only triple-transgenic models of AD that have both Aβ plaques and tau tangles and is also an accelerated mouse model of AD pathology onset. A specialized diet containing variable doses of PD2244 was given to 3xTg mice beginning at 6 months of age. The doses given were 0, 1, 3, 10, and 30 mg/kg of PD2244. Testing was then performed at 9, 12, and 15 months, where 15 months equated to thorough AD pathology. Regarding behavioral improvement, it was observed that all doses of PD2244 were effective to alleviate deficits in PPI at 9, 12, and 15 months of age. On the Barnes Maze, at 9 months of age the 10 mg/kg dose of PD2244 was effective to alleviate deficits, whereas at 12 months of age, 3 and 30 mg/kg dose of PD2244 was effective, and finally, at 15 months of age the 3, 10 and 30 mg/kg doses of PD2244 demonstrated efficacy to alleviate deficits in spatial memory performance. On the elevated T-maze, there were no effects at 9 months of age, but the 3 mg/kg dose of PD2244 resulted in anxiolytic effects at 12 and 15 months of age. Nest building behavior is also being observed in 15-month-old mice to determine effects of PD2244 on apathy since it is a common neuropsychiatric prodrome of AD. Finally, analysis of neurobiological markers has revealed that PD2244 reduced increases in the proinflammatory cytokines TNF-α and interkeukin-1β (IL-1β) at 15 months of age in the HPC. In addition, there is currently a project analyzing immunohistological staining of microglial cells in the HPC and PFC in 15-month-old animals. This project is designed to discover a novel, effective, anti-inflammatory treatment for cognitive deficits and increases in anxiety associate with AD

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway