| First Author | Jong Huat T | Year | 2024 |
| Journal | Sci Rep | Volume | 14 |
| Issue | 1 | Pages | 14305 |
| PubMed ID | 38906984 | Mgi Jnum | J:350176 |
| Mgi Id | MGI:7662019 | Doi | 10.1038/s41598-024-65248-1 |
| Citation | Jong Huat T, et al. (2024) The impact of astrocytic NF-kappaB on healthy and Alzheimer's disease brains. Sci Rep 14(1):14305 |
| abstractText | Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-kappaB (NF-kappaB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-kappaB function in astrocytes, we deepened the understanding of the role of astrocytic NF-kappaB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-kappaB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-kappaB and phosphorylated-p65 NF-kappaB in glial fibrillary acidic protein (GFAP)(+)-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-kappaB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-kappaB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16(INK4A) in neurons. However, in an AD mouse model, NF-kappaB inhibition accelerated beta-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-kappaB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-kappaB enables astrocytes' neuroprotective and neurotoxic responses in the brain. |
