Lessons from Microglia Aging for the Link between Inflammatory Bone Disorders and Alzheimer’s Disease

Figure 1

A schematic illustration of the transduction of signals from inflammatory bone diseases to brain-resident microglia through the leptomeninges and two different pathways for the IL-1β production activated by CGA and Aβ in microglia. In individuals with inflammatory bone diseases, IL-1β and TNF-α secreted by macrophages and periodontal bacterial components, including LPS, activate IL-1R/TNFR and TLRs localized on the surface of leptomeningeal cells to secrete IL-1β and TNF-α. IL-1β and TNF-α then stimulate both brain-resident microglia and neurons. After stimulation, the neuronal production and secretion of CGA and Aβ is increased. CGA and Aβ subsequently activate two different pathways for the IL-1β production in microglia, the NLRP3 inflammasome-CatB pathway via Aβ (open arrows), and the phagosome-CatB pathway via CGA (blue arrows). The NF-κB pathway activated during aging (red arrows) supports the production and secretion of IL-1β by Aβ. The leptomeningeal cell-neuron-microglia interactions form a vicious cycle of IL-1β production, culminating in the onset of cognitive impairment in AD.