Madison Carpenter

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

Improve patient outcomes with the CALS algorithm.

Zinc fingers consist of one of the most abundant motifs in transcription factors and DNA-binding proteins. Recent studies provide evidence on the pathological implication of zinc finger proteins in various neurodevelopmental disorders and malignancies but their role in pediatric brain tumors is largely unexplored. To this end, we investigated the differential expression of zinc finger-containing genes along with relevant biological processes and pathways among four main brain tumor categories (pilocytic astrocytomas, ependymomas, medulloblastomas and glioblastomas). By employing an extended bioinformatic toolset, we performed a preliminary in silico study in order to identify the expression of zinc finger-containing genes and associated functions in pediatric brain tumors. Our data analysis reveals the prominent role of C2H2-type zinc finger-containing genes in the molecular mechanisms underlying pediatric brain tumors followed by the Ring and PHD finger types. Significant dysregulation of ABLIM2 and UHFR1 genes was detected in all tumor types drawing attention to the dysregulation of cell polarization process and Ubiquitin-Proteasome System (UPS) in the pathogenesis of pediatric brain tumors. Moreover, significant gene clustering was observed in multiple locations with two highly visible clusters revealing a contrast in gene regulation between medulloblastomas and the other three brain tumor types, indicating a promising area of future research.

Abstract Description Genome-wide association studies (GWAS) in Alzheimer’s disease (AD) have identified over 200 diseased-associated genes that are predominantly expressed in microglia. While these studies implicate microglia in AD pathogenesis, the intrinsic role of AD risk genes in regulating microglia phenotype and function is unknown. Recent work has shown that microglia acquire a protective Disease-associated state, also known as DAM/MGnD when associated with Aβ-plaques. To identify how these GWAS-associated genes may regulate DAM/MGnD state, we developed an in vivo CRISPR screen that ex vivo introduces pools of sgRNAs into CAS9-GFP donor stem cells before intrathecal injecting these cells into P2-P4 5xFAD pups lacking microglia. After two months, these perturbed cells differentiated into functional microglia and completely repopulated the CNS, providing us with an ideal system to interrogate microglial biology in AD at scale. Our screen identified regulators of DAM/MGnD state, notably highlighting the known role of Tgfbr1, Mertk and Clec7a as potent inducers of this phenotype. Genetic deletion of Tim3, an immune checkpoint and recently identified AD-GWAS hit, showed a major effect in inducing a partial DAM/MGnD phenotype with reduction in plaque load and increase in synapse density. These studied validate our perturbation platform and provide a means by which to identify the role of other GWAS hits in microglial development and function in vivo. Topic Categories Neuroimmunology (NEUR)