Glia最新文献

Astrocytes critically influence ischemic stroke outcomes through calcium signaling-dependent mechanisms, which can be both beneficial and detrimental. Stromal interaction molecule 1 (STIM1), a key regulator of store-operated calcium entry, has emerged as an essential mediator of intracellular calcium dynamics in astrocytes, yet its role in acute stroke remains largely unknown. Here, we demonstrate that conditional knockout of astrocytic STIM1 in mice dramatically reduces infarct volume and improves neurological function following ischemic stroke. In vivo two-photon imaging revealed that astrocytic STIM1 knockout reduces the amplitude and duration of both spreading depolarization-associated and spontaneous calcium transients during acute ischemia. The reduction of these transients was highly correlated with improved neurological outcomes. Furthermore, the astrocytic STIM1 knockout mitigated excitotoxic stress by accelerating glutamate clearance and reducing total glutamate burden during ischemic stroke. Our findings establish astrocytic STIM1 as a critical regulator of calcium and glutamate dynamics during ischemic stroke, and therefore, targeting astrocytic STIM1 represents a promising therapeutic avenue for alleviating ischemic brain damage by reducing calcium overload and glutamate excitotoxicity.

RhoA is well known as a key molecular switch for cytoskeleton remodeling, and previous studies reveal RhoA plays a pivotal role in Schwann cell myelination which is highly dependent on the dynamics regulation of the actin and microtubule cytoskeleton. Existing evidence indicates RhoA modulates myelination and other biofunctions by targeting actin filament turnover; however, the role of RhoA in microtubule dynamics remains unknown. Herein, Bulk mRNA sequencing and bioinformatic analysis enriched microtubule dynamics-related ontology terms in RhoA knockout Schwann cells, and identified that microtubules contribute to RhoA deficiency-caused hypomyelination. Both in vivo and in vitro experiments demonstrated that genetic ablation or pharmacological inhibition of RhoA attenuates microtubule dynamics in Schwann cells, whereas activated RhoA overexpression or RhoA agonist enhances the microtubule dynamics. RhoA conditional knockout (cKO) in Schwann cells led to hypomyelination, dysmyelination and nerve functional deficits in mice. Mechanistically, the present study identified CDK2 as a crucial mediating molecule for RhoA regulating microtubule dynamics. CDK2 overexpression could reverse the reduced microtubule dynamics, hypomyelination and motor deficits in RhoA cKO mice. Furthermore, RhoA modulating CDK2 is dependent on YAP/TEAD signaling, and the ASPM/p60-Katanin axis mediates the role of CDK2 in controlling microtubule dynamics. Collectively, this study uncovered a novel RhoA/YAP1/TEAD3/CDK2/ASPM/p60-Katanin axis in regulating microtubule dynamics during Schwann cell myelination, which indicates that this pathway may be utilized as new targets for repairing congenital hypomyelination/dysmyelination neuropathy or peripheral nerve injury.

Neuroinflammation mediated by microglia and astrocytes is a major component of traumatic brain injury (TBI) pathophysiology. The sterile alpha and TIR motif containing 1 (SARM1) protein has been identified to play a key role in neurodegeneration and inflammatory cascades. Therefore, we hypothesized that the inhibition of SARM1 would prevent glial reactivity following TBI and could be targeted for therapeutic intervention. TBI was modeled in wild type (WT) and SARM1 knock-out (SARM1-KO) mice of both biological sexes by midline fluid percussion injury. At 7 or 28 days post-injury, brains were collected to examine glial reactivity via immunohistochemistry and compared to naïve controls. The density of microglia and glial fibrillary acidic protein (GFAP) immunoreactivity of astrocytes was significantly increased across time post-injury. Furthermore, microglial morphological changes and increased colocalization with a surrogate marker of phagocytosis (CD68) were evident at 7 days post-injury. In the absence of SARM1, microglial density and colocalization with CD68 was greater compared with WT animals, regardless of TBI. However, there were no differences in GFAP immunoreactivity with the genetic deletion of SARM1. When investigating biological sexes, the TBI-induced increase in microglial density and cell volume was greater in male mice at 7 days post-injury; however, microglia were more deramified in females. There were no significant differences in GFAP immunoreactivity between male and female mice. These results indicate that the genetic deletion of SARM1 is not sufficient to alter GFAP-labeling of astrocytes; however, SARM1 appears to impact microglial density and CD68 colocalization in the naïve and injured brain.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) are age-related disorders with similar pathological features, particularly insulin resistance and chronic inflammation. However, the primary drivers of insulin resistance in the AD brain remain debated. Although astrocytes and their metabolic functions have been increasingly implicated in AD, their specific role in brain insulin resistance is still unclear. In this study, we excluded peripheral metabolic confounders and focused on the alterations during a narrow time window surrounding amyloid-β (Aβ) plaque deposition in J20 mice. As Aβ pathology progressed, we observed a reduction in astrocyte numbers with increased morphological complexity. Furthermore, transcriptomic profiling demonstrated altered gene expression at synaptic, glial, and metabolic levels, along with a general suppression of insulin signaling pathways that indicated insulin resistance. Notably, we found a significant downregulation of serum and glucocorticoid-inducible kinase 1 (SGK1) and upregulation of insulin receptor substrate 2 (IRS2) expression, which diverged from the classic pattern observed in peripheral insulin resistance. We also detected a contradictory cytokine pattern in T-helper 17, where interleukin (IL)-6 and IL-17 levels were decreased in the hippocampus but elevated in the serum. This opposing trajectory suggests that astrocyte dysfunction and SGK1 downregulation have a critical role in immune signaling imbalance. Taken together, these findings highlight astrocyte depletion and/or dysfunction as key drivers of brain-specific insulin resistance and immune dysregulation in early AD, and that metabolic impairments in AD have a central nervous system-specific nature distinct from that in T2DM.