Search

The horizontal basal cells (HBCs) of olfactory epithelium (OE) serve as reservoirs for stem cells during OE regeneration, through proliferation and differentiation, which is important in recovery of olfactory function. However, the molecular mechanism of regulation of HBC proliferation and differentiation after injury remains unclear. Here, we found that yes-associated protein (YAP) was upregulated and activated in HBCs after OE injury. Deletion of YAP in HBCs led to impairment in OE regeneration and functional recovery of olfaction after injury. Mechanically, YAP was activated by S1P/S1PR2 signaling, thereby promoting the proliferation of HBCs and OE regeneration after injury. Finally, activation of YAP signaling enhanced the proliferation of HBCs and improved functional recovery of olfaction after OE injury or in Alzheimer's disease model mice. Taken together, these results reveal an S1P/S1PR2/YAP pathway in OE regeneration in response to injury, providing a promising therapeutic strategy for OE injury.

The depression is a mental disease that seriously affects the quality of life. It has complex pathophysiological characteristics, including neuroinflammation and apoptosis. Virgin coconut oil (VCO) is a natural food that has been found to have remarkable anti-inflammatory and anti-apoptotic properties. To further test the effects and mechanisms of VCO on depression based on the network pharmacological analysis and depression-like rat model, we found that VCO-treatment alleviated the depression-like behaviors, inhibited the activation of microglia and astrocytes, and reduced the loss of neurons in hippocampus, which may be due to decrease the apoptosis of neurons. Mechanically, network pharmacological analysis and western blotting showed that VCO might exert neuroprotective effects by activating Protein Kinase B (AKT)-related pathway. Taken together, our results identify unrecognized functions of VCO in depression, and further explore the underlying mechanism of depression.

Our aim was to examine whether the influence of apolipoprotein E4 (APOE4) genotype on cognitive decline differs in male and female across the Alzheimer's disease (AD) continuum. Among individuals with normal cognition (NC; n = 415), mild cognitive impairment (MCI; n = 870), and AD (n = 334), we investigated the longitudinal associations of APOE4 genotype and sex with cognitive decline over 13 years. Our cognitive outcomes were Rey Auditory Verbal Learning Test (RAVLT) total learning score and delayed recall and Mini-Mental State Examination (MMSE) score. There were significant effects of the APOE4×sex interaction on change in verbal memory in the MCI group, but not the NC or AD group. Specifically, among individuals with MCI, female APOE4 carriers had a steeper decline in RAVLT total learning score, but not delayed recall or MMSE score compared to all other groups (APOE4 + /Male, APOE4-/Female, APOE4-/Male). In conclusion, female APOE4 carriers have faster rates of memory decline than their male counterparts among MCI individuals.

Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAPGFAP-CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAPGFAP-CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-β (TGF-β) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β signaling pathway in YAPGFAP-CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAPGFAP-CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.

BackgroundOptic neuritis, inflammation of the optic nerve (ON), is one of the main symptoms in multiple sclerosis (MS) and leads to visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS. However, it remains unclear that the detailed roles and mechanisms of astrocytes in the neuroinflammation and demyelination in optic neuritis of MS. MethodsTo assess the role of YAP in ON and retina in response to experimental autoimmune encephalomyelitis (EAE), mice that conditionally knockout (CKO) YAP in astrocytes, namely YAP GFAP -CKO mice, were successfully generated. Immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, luxol fast blue (LFB) staining, electron microscopy (EM), qRT-PCR and gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the roles of YAP pathway in EAE based on these conditional knockout mice. Inhibitors including SRI-011381 [an agonist of transforming growth factor-β (TGF-β) pathway] and XMU-MP-1 (an inhibitor of Hippo kinase MST1/2 to activate YAP) were used to further explore the molecular mechanism of YAP in ON and retina of EAE mice. Additionally, microglia and retinal ganglion cells (RGCs) counts, and demyelination and astrocytes were assessed by immunohistological staining. ResultsWe found that yes-associated protein (YAP) was significantly upregulated and activated in the astrocytes of ON in EAE. Conditional knockout YAP in astrocytes caused more severe inflammatory infiltration and demyelination in ON, and damage of the RGCs in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of ON in EAE mice. Mechanically, TGF-β signaling pathway was significantly down-regulated after YAP deletion in astrocytes . Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-β 1 in YAP knockout ON astrocytes of EAE mice. Interestingly, SRI-011381 partially rescued the deficits in ON and retina of YAP knockout EAE mice. Finally, activation of YAP pathway relieved the neuroinflammation and demyelination in optic neuritis of EAE mice. ConclusionsThese results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-β signaling and provide targets for the development of therapeutic strategies tailored for optic neuritis in MS.

Axonal degeneration is a common pathological feature in many acute and chronic neurological diseases such as spinal cord injury (SCI). SARM1 (sterile alpha and TIR motif-containing 1), the fifth TLR (Toll-like receptor) adaptor, has diverse functions in the immune and nervous systems, and recently has been identified as a key mediator of Wallerian degeneration (WD). However, the detailed functions of SARM1 after SCI still remain unclear. Methods: Modified Allen's method was used to establish a contusion model of SCI in mice. Furthermore, to address the function of SARM1 after SCI, conditional knockout (CKO) mice in the central nervous system (CNS), SARM1Nestin-CKO mice, and SARM1GFAP-CKO mice were successfully generated by Nestin-Cre and GFAP-Cre transgenic mice crossed with SARM1flox/flox mice, respectively. Immunostaining, Hematoxylin-Eosin (HE) staining, Nissl staining and behavioral test assays such as footprint and Basso Mouse Scale (BMS) scoring were used to examine the roles of SARM1 pathway in SCI based on these conditional knockout mice. Drugs such as FK866, an inhibitor of SARM1, and apoptozole, an inhibitor of heat shock protein 70 (HSP70), were used to further explore the molecular mechanism of SARM1 in neural regeneration after SCI. Results: We found that SARM1 was upregulated in neurons and astrocytes at early stage after SCI. SARM1Nestin-CKO and SARM1GFAP-CKO mice displayed normal development of the spinal cords and motor function. Interestingly, conditional deletion of SARM1 in neurons and astrocytes promoted the functional recovery of behavior performance after SCI. Mechanistically, conditional deletion of SARM1 in neurons and astrocytes promoted neuronal regeneration at intermediate phase after SCI, and reduced neuroinflammation at SCI early phase through downregulation of NF-κB signaling after SCI, which may be due to upregulation of HSP70. Finally, FK866, an inhibitor of SARM1, reduced the neuroinflammation and promoted the neuronal regeneration after SCI. Conclusion: Our results indicate that SARM1-mediated prodegenerative pathway and neuroinflammation promotes the pathological progress of SCI and anti-SARM1 therapeutics are viable and promising approaches for preserving neuronal function after SCI.

Objective: To investigate whether APOE ε4 affects the association of verbal memory with neurodegeneration presented by the hippocampal volume/intracranial volume ratio (HpVR). Methods: The study sample included 371 individuals with normal cognition (NC), 725 subjects with amnestic mild cognitive impairment (aMCI), and 251 patients with mild Alzheimer's disease (AD) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) who underwent the rey auditory verbal learning test (RAVLT). Multiple linear regression models were conducted to assess the effect of the APOE ε4∗HpVR interaction on RAVLT in all subjects and in each diagnostic group adjusting for age, gender and educational attainment, and global cognition. Results: In all subjects, there was no significant APOE ε4 × HpVR interaction for immediate recall or delayed recall (p > 0.05). However, in aMCI subjects, there was a significant APOE ε4 × HpVR interaction for delayed recall (p = 0.008), but not immediate recall (p = 0.15). More specifically, the detrimental effect of APOE ε4 on delayed recall altered by HpVR such that this effect was most evident among subjects with small to moderate HpVR, but this disadvantage was absent or even reversed among subjects with larger HpVR. No significant interaction was observed in the NC or AD group. Conclusion: These findings highlight a potential role of APOE ε4 status in affecting the association of hippocampus size with delayed recall memory in the early stage of AD.

The traditional ant colony algorithm is based on the positive feedback mechanism. In essence, this guidance is conducive to the convergence of the algorithm but is not conducive to the diversity of the search. In order to shorten the length of the path of the optimization, this paper proposes an improved ant colony algorithm to improve search diversity. The algorithm, the positive feedback, the inverse feedback simultaneously makes the entire ant colony search time is greatly reduced, and will greatly increase the diversity of the ant colony search space and search results. Simulation results of the TSP problem show that, the new algorithm for solving complex combinatorial optimization problem has a significant effect.