Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events

Abstract

Massive neuronal loss is a key pathological hallmark of Alzheimer's disease (AD). However, the mechanisms are still unclear. Here we demonstrate that neuroinflammation, cell autonomous to microglia, is capable of inducing neuronal cell cycle events (CCEs), which are toxic for terminally differentiated neurons. First, oligomeric amyloid-beta peptide (AβO)-mediated microglial activation induced neuronal CCEs via the tumor-necrosis factor-α (TNFα) and the c-Jun Kinase (JNK) signaling pathway. Second, adoptive transfer of CD11b+ microglia from AD transgenic mice (R1.40) induced neuronal cyclin D1 expression via TNFα signaling pathway. Third, genetic deficiency of TNFα in R1.40 mice (R1.40-Tnfα(-/-)) failed to induce neuronal CCEs. Finally, the mitotically active neurons spatially co-exist with F4/80+ activated microglia in the human AD brain and that a portion of these neurons are apoptotic. Together our data suggest a cell-autonomous role of microglia, and identify TNFα as the responsible cytokine, in promoting neuronal CCEs in the pathogenesis of AD.

Keywords: AD; Adoptive transfer; Alzheimer's disease; AβF; AβO; BrdU; Bromodeoxyuridine; CCE; CM; COX2; GFP; IDV; IKKα/β; IL-1β; IL-6; INFγ; IκB kinase α/β; JNK; LPS; MAP2; Microglia; NOS; NSAID; Neuroinflammation; Neuronal cell cycle; PAS; PBS; PCNA; PFA; PI3K; Phosphatidylinositol 3-kinase; ROI; RT; STAT3; Signal transducer and activator of transcription 3; TNF receptor; TNFR; TNFα; TUNEL; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Tumor Necrosis Factor-α; Tumor necrosis factor-α (TNFα); c-Jun Kinase; c-Jun Kinase (JNK); cell cycle events; conditioned media; cyclooxygenase-2; fibrillar amyloid-beta peptide; green fluorescent protein; integrated density value; interferon-γ; interleukin-1β; interleukin-6; lipopolysaccharide; microtubule associated protein-2; nitric oxide synthase; non-steroidal anti-inflammatory drug; oligomeric amyloid-beta peptide; p38 MAPK; p38 mitogen activated protein kinase; paraformaldehyde; phosphate buffered saline; proliferating cell nuclear antigen; protein-A-sepharose; region of interest; room temperature.