IKKβ Deficiency in Myeloid Cells Ameliorates Alzheimer's Disease-Related Symptoms and Pathology

• DOI: 10.1523/jneurosci.1348-14.2014
• Publication Date: 2014-09-24T16:58:27Z
• Authors: Yang Liu; Xu Liu; Wenlin Hao; Yann Decker; Robert Schomburg; Livia Fülöp; Manolis Pasparakis; Michael D. Menger; Klaus Fassbender
• Keywords: 0301 basic medicine; Amyloid beta-Peptides; Plaque, Amyloid; I-kappa B Kinase; 3. Good health; Mice, Inbred C57BL; Mice; Protein Transport; 03 medical and health sciences; Alzheimer Disease; Animals; Humans; Myeloid Cells; Microglia; Cells, Cultured; Gene Deletion

Alzheimer's disease (AD) is characterized by extracellular amyloid-β (Aβ) deposits and microglia-dominated inflammatory activation. Innate immune signaling controls microglial inflammatory activities and Aβ clearance. However, studies examining innate immunity in Aβ pathology and neuronal degeneration have produced conflicting results. In this study, we investigated the pathogenic role of innate immunity in AD by ablating a key signaling molecule, IKKβ, specifically in the myeloid cells of TgCRND8 APP-transgenic mice. Deficiency of IKKβ in myeloid cells, especially microglia, simultaneously reduced inflammatory activation and Aβ load in the brain and these effects were associated with reduction of cognitive deficits and preservation of synaptic structure proteins. IKKβ deficiency enhanced microglial recruitment to Aβ deposits and facilitated Aβ internalization, perhaps by inhibiting TGF-β-SMAD2/3 signaling, but did not affect Aβ production and efflux. Therefore, inhibition of IKKβ signaling in myeloid cells improves cognitive functions in AD mice by reducing inflammatory activation and enhancing Aβ clearance. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying AD progression.