The impact of astrocytic NF-κB on healthy and Alzheimer’s disease brains

• Published in: Scientific reports 2024-06, Vol.14 (1), p.14305-14, Article 14305
• Main Authors: Jong Huat, Tee, Camats-Perna, Judith, Newcombe, Estella A., Onraet, Tessa, Campbell, Daniel, Sucic, Josiah T., Martini, Alessandra, Forner, Stefânia, Mirzaei, Mehdi, Poon, Wayne, LaFerla, Frank M., Medeiros, Rodrigo
• Format: Article
• Language: English
• Subjects: 631/378/2596/1308; 692/617/375/132/1283; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animal models; Animals; Aquaporin 4; Astrocytes; Astrocytes - metabolism; Brain; Brain - metabolism; Brain - pathology; Cognitive ability; Disease Models, Animal; Female; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; Humanities and Social Sciences; Humans; Inflammation; INK4a protein; Male; Mice; Molecular biology; multidisciplinary; Neurodegenerative diseases; Neuroprotection; Neurotoxicity; NF-kappa B - metabolism; NF-κB protein; p16 Protein; Proteins; Proteomics; Science; Science (multidisciplinary); Senescence; Signal Transduction; Tau protein; Transcriptomics; β-Amyloid
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-65248-1

Astrocytes play a role in healthy cognitive function and Alzheimer’s disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP) + -astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB 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-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB 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-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.