Kyungdeok Kim and al.

Meningeal lymphatics serve as an outlet for cerebrospinal fluid, and their dysfunction is associated with various neurodegenerative conditions. Previous studies have demonstrated that dysfunctional meningeal lymphatics evoke behavioral changes, but the neural mechanisms underlying these changes have remained elusive. Here, the authors show that prolonged impairment of meningeal lymphatics alters the balance of cortical excitatory and inhibitory synaptic inputs, accompanied by deficits in memory tasks. These synaptic and behavioral alterations induced by lymphatic dysfunction are mediated by microglia, leading to increased expression of the interleukin 6 gene (Il6). IL-6 drives inhibitory synapse phenotypes via a combination of trans- and classical IL-6 signaling. Restoring meningeal lymphatic function in aged mice reverses age-associated synaptic and behavioral alterations. Our findings suggest that dysfunctional meningeal lymphatics adversely impact cortical circuitry through an IL-6-dependent mechanism and identify a potential target for treating aging-associated cognitive decline.

Zonghua Li and al.

The apolipoprotein E (APOE) gene is the strongest genetic risk modifier for Alzheimer’s disease (AD), with the APOE4 allele increasing risk and APOE2 decreasing it compared with the common APOE3 allele. Using single-nucleus RNA sequencing of the temporal cortex from APOE2 carriers, APOE3 homozygotes, and APOE4 carriers, the authors found that AD-associated transcriptomic changes were highly APOE genotype dependent. Comparing AD with controls, APOE2 carriers showed upregulated synaptic and myelination-related pathways, preserving synapses and myelination at the protein level. Conversely, these pathways were downregulated in APOE3 homozygotes, resulting in reduced synaptic and myelination proteins. In APOE4 carriers, excitatory neurons displayed reduced synaptic pathways similar to APOE3, but oligodendrocytes showed upregulated myelination pathways like APOE2. However, their synaptic and myelination protein levels remained unchanged or increased. APOE4 carriers also showed increased pro-inflammatory signatures in microglia but reduced responses to amyloid-β pathology. These findings reveal APOE genotype-specific molecular alterations in AD across cell types.

Jessica C. Hargarten and al.

Therapies to reduce neuroinflammation following resolution of acute central nervous system (CNS) infections are urgently needed, particularly for patients with non–HIV-associated cryptococcal meningoencephalitis complicated by a postinfectious inflammatory response syndrome (cPIIRS). To identify druggable targets in cPIIRS, patient cerebral spinal fluid samples underwent transcriptional analysis, revealing a Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway dominance in neuroinflammatory gene signatures. MurinecPIIRS models recapitulated this pathway predominance and treatment with the JAK inhibitor ruxolitinib, confirmed a mechanistic requirement for this pathway in disease pathology. Ruxolitinib treatment improved markers of neuronal damage, reduced activated T cell and myeloid cells, and improved weight. On the basis of these findings, we conducted a first-in-human ruxolitinib treatment of patients with cPIIRS (NCT00001352). Ruxolitinib treatment of six patients led to demonstrated tolerability, reductions in inflammatory biomarkers and activated immune cells, and improved brain imaging. These results advocate for pathway-instructed therapeutics in neuroinflammatory diseases and endorse JAK inhibitors in further clinical studies of cPIIRS.

Itay Raphael and al.

The authors report a large-scale comprehensive examination of the TCR landscape of tumor-infiltrating lymphocytes (TILs) across the spectrum of pediatric brain tumors, the leading cause of cancer-related mortality in children. They show that a T cell clonality index can inform patient prognosis, where more clonality is associated with more favorable outcomes. Moreover, TCR similarity groups’ assessment revealed patient clusters with defined human leukocyte antigen associations. Computational analysis of these clusters identified putative tumor antigens and peptides as targets for antitumor T cell immunity, which were functionally validated by T cell stimulation assays in vitro. Together, this study presents a framework for tumor antigen prediction based on in situ and in silico TIL TCR analyses.

Kaicheng Xu and al.

The authors developed a cell/drug-free strategy to selectively boost endogenous sensory innervation to harness immune responses for promoting tissue rehabilitation. Specifically, a dual-functional phage was constructed with a sensory nerve–homing peptide and a β-subunit of nerve growth factor (β-NGF)–binding peptide. These double-displayed phages captured endogenic β-NGF and localized to sensory nerves to promote sensory innervation. Furthermore, regarding bone regeneration, phage-loaded hydrogels achieved rapid sensory nerve ingrowth in bone defect areas. Mechanistically, sensory neurotization facilitated M2 macrophage polarization of macrophages through the Sema3A/XIAP/PAX6 pathway, thus decreasing the M1/M2 ratio to induce the dissipation of local inflammation.