Sacilotto, Patricia

Abstract Introduction Colony stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is an early onset neurodegenerative disease characterized by microglial deficits, abnormal glial responses, white matter pathology, and severe motor and cognitive decline. Methods At 8 months, mice lacking two copies of the Csf1r gene Fms-intronic regulatory element (FIRE) recapitulate some of the brain pathological features of CSF1R-related leukoencephalopathy, namely the deficits in microglia, astrogliosis, and demyelination. Of note, we detected deficits in lymphatic vasculature and altered macrophage activation in the meninges of Csf1rΔFIRE/ΔFIRE mice by flow, prior to the appearance of brain gliosis, neuronal dystrophy, and fine motor impairment. Results Eliminating the remainder CSF1R-expressing innate immune cells, including border-associated macrophages (BAMs), with PLX5622 at 2 months reshaped the immune crosstalk at the meningeal dura and restored lymphatic vascular expansion in Csf1rΔFIRE/ΔFIRE mice Conclusion Ongoing experiments in the lab will clarify the exact mechanisms through which dysfunctional innate immunity at the brain-meningeal interface and lack of meningeal lymphatic vasculature contribute to the development of brain pathology and impaired motor behavior in this model of CSF1R-related leukoencephalopathy. This work has unveiled novel molecular insights involving the meningeal lymphatic system that might be of therapeutic relevance to canonical central nervous system white matter diseases. Funding Source n/a Topic Categories Neuroimmunology (NEUR)

Abstract Background Apolipoprotein E (apoE) facilitates the fibrillization and deposition of amyloid β (Aβ) in Alzheimer's Disease (AD). Supported by robust literature from various groups, in our current study we have investigated the relative amyloidogenic properties of the three major human APOE alleles. Knowledge from such studies could provide insight into the role of ApoE protein in the deposition, evolution and maturation of parenchymal Aβ. Method We used hAbetaSAA (Jax Labs) mice crossed with human APOE targeted replacement mice to create hAbetaSAA mice homozygous for human APOE E2, E3 and E4 . Furthermore, APPsi mice (hAPPswe/indiana: Borchelt) expressing human APOE E3 or E4 were injected intracerebrally with AD brain lysates to examine the role of APOE genotype on Aβ seeding. Neuropathological examination was conducted via immunohistochemistry, immunofluorescence and immunoblotting. Result hAbetaSAA mice expressing human APOE E4 showed higher Aβ deposition relative to APOE E3 and APOE E2 by 5 months of age and progressing through 8 months and 13 months of age. In comparison, APP mice expressing humanized Aβ (Jax Labs) with human APOE E4 did not develop deposits in their lifetime. hAbetaSAA mice with endogenous mouse Apoe had the highest Aβ plaque deposition, with an approximately 60‐fold increase in Aβ burden compared to SAA APP mice expressing APOE E3 , especially in the earlier deposition phase. Removing mouse Apoe resulted in dose‐dependent reduction in Aβ deposition, consistent with previously published literature. Plaque morphology did not show any notable differences between APOE genotypes, and colocalization of apoE with Aβ were relatively equivalent across different APOE genotypes. Further, in the APPsi model seeded with AD‐derived seeds, we found that mice with APOE E4 or APOE E3 developed equal burdens of diffuse parenchymal Aβ, with no detectable changes in plaque morphology. Conclusion We conclude that apoE variants broadly influence the rate of amyloid deposition, but do not modify the morphology of the resulting deposits or colocalization with Aβ. Notably, when seeding with AD patient brain lysate, there was no significant difference in Aβ burden between APPsi mice expressing APOE E3 and E4 . Our study adds insights into the role of apoE isoforms in determining Aβ‐related phenotype.