Lin Wang and al.

To systematically understand age-induced molecular changes, the authors performed spatial transcriptomics of young, middle-aged, and old mouse brains and identified seven transcriptionally distinct regions. All regions exhibited age-associated upregulation of inflammatory mRNAs and downregulation of mRNAs related to synaptic function. Notably, aging white matter fiber tracts showed the most prominent changes with pronounced effects in females. The inflammatory signatures indicated major ongoing events : microglia activation, astrogliosis, complement activation, and myeloid cell infiltration. Immunofluorescence and quantitative MRI analyses confirmed physical interaction of activated microglia with fiber tracts and concomitant reduction of myelin in old mice. In silico analyses identified potential transcription factors influencing these changes.

Zhen Tang and al.

The authors show that STING mediates a neuroinflammatory gene signature in three distinct lysosomal storage disorders (LSD) mouse models, Galctwi/twi, Ppt1−/−, and Cln7−/−. Transcriptomic analysis of Galctwi/twi mouse brain tissue revealed that STING also mediates the expression of lysosomal genes that are regulated by the transcriptional factor TFEB. Immunohistochemical and scRNA-seq analyses show that STING regulates lysosomal gene expression in microglia. Mechanistically, STING activation leads to TFEB dephosphorylation, nuclear translocation, and expression of lysosomal genes. This process is independent of immune signaling. Furthermore, we show that the STING-TFEB axis facilitates lysosomal repair. Together, our data identify STING-TFEB as a lysosomal quality control mechanism that responds to lysosomal dysfunction.

Pan Wang and al.

The authors employed the spatial transcriptomics technique Stereo-seq combined with scRNA-seq to investigate the gene expression and cell composition changes in human hippocampus with or without Alzheimer’s disease (AD). The transcriptomic map, with single-cell precision, unveiled AD-associated alterations with spatial specificity, which include the following: (1) elevated synapse pruning gene expression in the fimbria of AD, with disrupted microglia-astrocyte communication likely leading to disorganized synaptic structure; (2) a globally increased energy generation in the cornu ammonis (CA) region, with varying degrees across its subregions; (3) a significant reduction in the number of CA1 neurons in AD, while CA4 neurons remained largely unaffected, potentially due to gene alterations in CA4 conferring resilience to AD; and (4) aggravated amyloid-beta (Aβ) plaques in CA1 and stratum lucidum, radiatum, and moleculare (SLRM). Integration of Stereo-seq map with Aβ staining revealed a sequential enrichment of microglia and astrocytes around Aβ plaques. Finally, reduced brain-derived extracellular vesicles carrying cholecystokinin (CCK) and peripheral myelin protein 2 (PMP2) in AD plasma highlighted their diagnostic potential for clinical applications.

Xin Feng and al.

Alzheimer disease (AD) therapy may benefit from optimized approaches to inhibit neuroinflammation. Small-molecule inhibitors of PKR, a proinflammatory kinase activated by double-stranded RNA (dsRNA) have efficacy in AD models but their utility is compromised by adverse side effects. Here, the authors targeted PKR in two mouse models of AD using circular RNAs containing short double-stranded regions (ds-cRNAs), which are structurally similar to what the authors used previously to target PKR in psoriasis models. The present data show that the intrahippocampal injection of ds-cRNAs targeting neurons and microglia via an adeno-associated virus (AAV) effectively dampens excessive PKR activity and reduces neuroinflammation and amyloid-β plaques with minimal toxicity. When delivered to the whole brain via intravenous injection of a modified AAV crossing the blood–brain barrier, ds-cRNAs exerted neuroprotection and enhanced the capability of spatial learning and memory in AD mouse models. The delivery of ds-cRNAs at different stages ine these AD models alleviated disease phenotypes, with sustained therapeutic effects for at least 6 months after a single administration.

Guiping Kong and al.

Spinal cord injury (SCI) increasingly affects aged individuals, where functional impairment and mortality are highest. However, the aging-dependent mechanisms underpinning tissue damage remain elusive. Here, the authors found that NK-like T cells (NKLT) seed the intact aged human and murine spinal cord and multiply further after injury. NKLT cells accumulate in the spinal cord via CXCR6 and CXCL16 signaling to clonally expand by engaging with MHC -I-expressing myeloid cells. NKLT cells expressing Nkg7 disrupt myeloid-cell-dependent wound healing in the aged injured cord. Nkg7 deletion in mice curbs NKLT cell degranulation to normalize the myeloid cell phenotype, thus promoting tissue repair and axonal integrity. Monoclonal antibodies neutralizing CD8⁺ T cells after SCI enhance neurological recovery by promoting wound healing