Inhibiting mtDNA‐STING‐NLRP3/IL‐1β axis‐mediated neutrophil infiltration protects neurons in Alzheimer's disease

Abstract

Neutrophil is a pathophysiological character in Alzheimer's disease. The pathogen for neutrophil activation in cerebral tissue is the accumulated amyloid protein. In our present study, neutrophils infiltrate into the cerebra in two models (transgenic model APP/PS1 and stereotactic injection model) and promote neuron apoptosis, releasing their cellular constituents, including mitochondria and mitochondrial DNA (mtDNA). We found that both Aβ1–42 and mtDNA could provoke neutrophil infiltration into the cerebra, and they had synergistic effects when they presented together. This neutrophillic neuroinflammation upregulates expressions of STING, NLRP3 and IL‐1β. These inflammatory cytokines with mtDNA constitute the mtDNA‐STING‐NLRP3/IL‐1β axis, which is the prerequisite for neutrophil infiltration. When any factor in this pathway is depleted, the migration of neutrophils into cerebral tissue is ceased, with neurons and cognitive function being protected. Thus, we provide a novel perspective to alleviate the progression of Alzheimer's disease.

Promotive effect of skin precursor-derived Schwann cells on brachial plexus neurotomy and motor neuron damage repair through milieu-regulating secretome

“…Intriguingly, each HRCK as signal target may initiate diverse biological process regulation of implicated endogenous cell types in neural microenvironment. For instance, Fractalkine (namely chemokine (C-X3-C motif) ligand 1, CX3CL1) was identified as a signal inducing microglia-mediated synapse elimination to regulate synaptic connectivity [ 44 ] and mitigating inflammation [ 45 ]; Intercellular adhesion molecule-1 (ICAM-1) was reported could protect neurons against Amyloid-β and improve cognitive behaviors in mice by inhibiting NF-κB [ 46 ]; Monocyte chemoattractant protein-1 alpha (MCP-1α, namely chemokine (C–C motif) ligand 2, CCL2) has been identified involved in the autophagy and apoptosis signaling pathway axis after spinal cord injury [ 47 ]; Notch1 signaling pathway has been reported could promote angiogenesis of cerebral microvasculature to protect ischemia reperfusion injury [ 48 ]; Soluble tumor necrosis factor-alpha (TNF-α) selectively inhibition was reported could change the neuroinflammatory response after moderate spinal cord injury in mice [ 49 ]; Interleukin-1 alpha (IL-1α) preconditioned mesenchymal stem cells exhibited promotive neuroprotection properties for ischemic stroke mice [ 50 ]; while IL-1β was reported as inhibitory target in inflammsome axis-mediated neutrophil infiltration could protect neurons in neurodegenerative disease [ 51 ]; PDGF-AA has been reported could improve the function recovery of spinal cord injury via subcutaneous administration [ 52 ]; and VEGF-A has been reviewed as the leading promoter of angiogenesis in health and disease, thus became the therapeutic targeting [ 53 ]. Therefore, the possible modulation effect of HRCK on neuronal and non-neuronal cells in neural injury position was especially concerned in our multiple cluster analyses.…”

Saponin components in Polygala tenuifolia as potential candidate drugs for treating dementia

“…Excessive secretion of Aβ protein can damage central nervous system cells ( Xia et al, 2024 ). Aβ protein is produced through the enzymatic cleavage of amyloid precursor protein (APP), which is encoded by the APP gene located on chromosome 21 ( Maurya et al, 2023 ).…”