Journal of Neuroinflammation最新文献

Background: Alzheimer's disease (AD) is the leading cause of dementia in the US, with over 80% of affected individuals experiencing comorbid metabolic disease. Along with age and sex, metabolic syndrome and prediabetes are known risk factors for developing dementia and AD, highlighting the complex nature of the disease. How these risk factors affect cerebral amyloid angiopathy (CAA) is less well studied. As such, we examined the effect of diet-induced metabolic syndrome and sex on cognition, neuroinflammation, and pathology in the Tg-SwDI mouse model of AD and CAA.

Methods: Male and female Tg-SwDI and WT mice were fed a low fat (LFD; 10% fat) or high fat (HFD; 60% fat) diet from 3 to 10 months of age. Metabolic, cognitive, and neuropathology outcomes were assessed.

Results: All HFD-fed mice gained weight and exhibited impaired glucose tolerance. Metabolic disturbances were most severe in AD females receiving HFD. In both males and females, HFD-fed AD mice showed increased anxiety-like behavior, decreased locomotor activity, and impaired recognition memory in the open field and novel object recognition tests, respectively. HFD-fed AD females specifically exhibited spatial memory deficits in the Barnes maze. Hippocampal microgliosis, activated microglia, and astrogliosis were more severe in AD mice, HFD decreased hippocampal microgliosis and astrogliosis but increased cytokine and chemokine expression in AD females. HFD-fed AD females had greater β-amyloid plaques and CAA in the thalamus compared to LFD-fed AD controls. All metrics of neuroinflammation significantly correlated with CAA pathology in the thalamus.

Conclusion: AD females experienced greater metabolic, cognitive, and pathologic effects in response to a HFD compared to AD males and WT controls. These observations provide a better understanding of how metabolic disease may differentially affect the development of dementia in men and women.

Background: Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is a major determinant of poor outcomes, yet its molecular mechanisms remain incompletely understood. Neuroinflammation and neuronal death are key pathological features, but the specific signaling pathways linking glial activation to neuronal demise are unclear.

Methods: Using a murine pre-chiasmatic SAH model, we employed CCR5 knockout mice, astrocyte-specific Ccl5 knockdown (via AAV-GFAP-shRNA), pharmacological CCR5 inhibition (Maraviroc), and recombinant CCL5 (rCCL5) administration. Neurological function was assessed. Molecular pathways were examined by qPCR, immunofluorescence, Western blot, and ELISA. The clinical relevance was evaluated in cerebrospinal fluid (CSF) from SAH patients.

Results: We identified a significant upregulation of CCR5, predominantly in hippocampal neurons, after SAH. Its genetic or pharmacological inhibition attenuated neuronal necroptosis, preserved synaptic integrity, and improved neurobehavioral outcomes. We further demonstrated that the CCR5 ligand CCL5 was primarily released by activated astrocytes. CCR5 ablation reversed the neurotoxicity-exacerbating effect of exogenous rCCL5. Mechanistically, the CCL5/CCR5 axis triggered NF-κB activation, leading to TNF-α/IL-1β production and subsequent p-RIPK3/p-MLKL-mediated neuronal necroptosis. Critically, CSF levels of CCL5 and CCR5 from 41 SAH patients and 22 controls were associated with disease severity and poor prognosis, underscoring its translational significance.

Conclusion: Our study unveils that astrocytic CCL5 orchestrates CCR5-dependent neuronal necroptosis via NF-κB/p-RIPK3/p-MLKL signaling, thereby driving EBI after SAH. These findings establish the CCL5/CCR5 axis as a potential therapeutic target for mitigating brain injury and cognitive dysfunction in SAH patients.

Spinal cord injury is a severe neurological condition associated with an increased risk of infection, an elevated mortality rate, and often results in chronic neuropathic pain. The peripheral immune changes in the chronic phase of spinal cord injury are largely unknown, as is their capacity to facilitate neuropathic pain. The current study used a high-dimensional single-cell analysis of peripheral blood to evaluate major immune populations and functional markers in individuals with chronic spinal injury. Spinal cord injury was associated with a shift towards classical monocytes and an increase in granulocytic myeloid-derived suppressor cells. There were also reductions in NK cells and B cells, as well as impairments to memory T cell functioning. The elevation of classical monocytes and decrease in NK cells were more pronounced in injured individuals with neuropathic pain, a high spinal level of lesion, and a moderate, but not severe injury. These findings highlight the cell-specific systemic immune dysfunction in chronic spinal cord injury and how more severe clinical subgroups are largely associated with greater immune impairment. Therefore, targeting immune dysfunction may lead to an improvement in symptom severity, whilst biomarkers of immune dysfunction may be useful in predicting the clinical trajectory.