Fig. 7.

Schematic representation of the role of NF-κB in AD pathology and the sites of action of GA: In health, a homeostatic balance between activated c-rel containing dimers and the p65:p50 dimers plays a role in maintaining synaptic activity, neuronal plasticity, and health. In susceptible individuals, age-related noxious stimuli activate NF-κB p65 in neuronal cells, increase transactivation of BACE-1 and consequently Aβ generation. Stimulation and NF-κB p65 activation in glial cells lead to increased secretion of proinflammatory genes (such as IL-12, IL-17), proapoptotic genes and neurotoxic factors (glutamate, iNOS). A feed forward loop ensues culminating in neurodegeneration. By selectively targeting activated p65, GA edges the disrupted balance toward the homeostatic level. The insight shows the rationale for the efficacy of GA: an attempt to re-establish the NF-κB homeostasis and suppress excessive glial activation. Abbreviations: NF-κB, nuclear factor-kappa B; GA, glucocorticoid induced leucine zipper analog; Aβ, amyloid β; AD, Alzheimer’s disease; BACE-1, β secretase-1; iNOS, induced nitric oxide synthase; IL, interleukin.