SORBS1/FBXO22/BAG3 Axis Drives Astrocyte Senescence via Calcium Signaling, Exacerbating Alzheimer's Neuronal Damage

In Alzheimer's disease (AD), senescent astrocytes are key drivers of neuroinflammation and neuronal damage, primarily through the senescence-associated secretory phenotype (SASP). While calcium signaling is known to be crucial in this process, the precise molecular mechanisms linking it to astrocyte senescence and AD pathology have remained largely undefined. Current AD treatments often fail to address the underlying cellular senescence and neuroinflammatory cascades, highlighting a critical gap for novel therapeutic targets that can modulate glial cell health and function.

Researchers utilized scRNA-seq data from AD and control brains (Gene Expression Omnibus) to identify astrocyte sub-clusters and senescence-related genes via pseudotime trajectory and differential expression analyses. An in vitro AD model was established by treating astrocytes with amyloid-β (Aβ). Astrocyte senescence was assessed using SA-β-gal staining, qRT-PCR, Western blot for senescence markers, and ELISA for SASP cytokines. Intracellular Ca2+ levels were measured with Fluo-4 AM probes. Bioinformatic screening predicted protein interactions, which were validated using Co-IP and in vitro ubiquitination assays. Finally, an astrocyte-neuron co-culture model was used to evaluate neuronal damage via MTT assay, AChE activity kits, Western blot for AD-phenotype proteins, flow cytometry for apoptosis, and ELISA for inflammatory factors.

Single-cell RNA-seq analysis revealed a marked reduction in astrocyte expression in AD brains, suggesting a link to cellular senescence. The SASP gene SORBS1 was selectively up-regulated in astrocytes and significantly enriched in calcium-signaling pathways. Functional assays confirmed that SORBS1 accelerated astrocyte senescence in vitro. Mechanistically, the study found that SORBS1 directly interacted with FBXO22 to promote the ubiquitin-dependent degradation of BAG3. This degradation of BAG3 subsequently amplified calcium signaling within astrocytes. This amplification of calcium signaling was shown to accelerate astrocyte senescence and significantly contribute to AD-related neuronal damage in co-culture models. The identified SORBS1/FBXO22/BAG3 axis represents a novel molecular pathway driving astrocyte dysfunction in AD.

The SORBS1/FBXO22/BAG3 axis drives astrocyte senescence by amplifying calcium signaling, leading to increased neuronal damage in Alzheimer's disease models.