Altered Myeloid Microglia Improve Alzheimer's Symptoms
Growing amounts of amyloid-β (Aβ) between cells forms one part of the pathology of Alzheimer's disease. This is a dynamic process, as much a matter of reduced clearance rates as increased production or simple accumulation: there are systems in the body capable of clearing out this amyloid and which can in theory be altered to increase clearance rates. One part of the puzzle of what makes Alzheimer's disease an age-related condition is why exactly these clearance mechanisms fail with advancing aging: which of the known forms of cellular and molecular damage associated with aging cause this to happen? These researchers are working with microglia, supporting cells of the innate immune system present in the brain, with an eye to producing therapies to enhance amyloid clearance:
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 [a mouse model of Alzheimer's disease]. 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.