A large body of literature supports the idea that nuclear factor kappa B (NF-κB) signaling contributes to not only immunity, but also inflammation, cancer, and nervous system function. However, studies on NF-κB activity in mitochondrial function are much more limited and scattered throughout the literature. For example, in 2001 it was first published that NF-κB subunits were found in the mitochondria, including not only IkBα and NF-κB p65 subunits, but also NF-κB pathway proteins such as IKKα, IKKβ, and IKKγ, but not much follow-up work has been done to date. Upon further thought the lack of studies on NF-κB activity in mitochondrial function is surprising given the importance and the evolutionary history of both NF-κB and the mitochondrion. Both are ancient in their appearance in our biological record where both contribute substantially to cell survival, cell death, and the regulation of function and/or disease. Studies also show NF-κB can influence mitochondrial function from outside the mitochondria. Therefore, it is essential to understand the complexity of these roles both inside and out of this organelle. In this review, an attempt is made to understand how NF-κB activity contributes to overall mitochondrial function - both inside and out. The discussion at times is speculative and perhaps even provocative to some, since NF-κB does not yet have defined mitochondrial targeting sequences for some nuclear-encoded mitochondrial genes and mechanisms of mitochondrial import for NF-κB are not yet entirely understood. Also, the data associated with the mitochondrial localization of proteins must be yet further proved with additional experiments.

Although better known for its role in inflammation, the transcription factor nuclear factor kappa B (NF-κB) has more recently been implicated in synaptic plasticity, learning, and memory. This has been, in part, to the discovery of its localization not just in glia, cells that are integral to mediating the inflammatory process in the brain, but also neurons. Several effectors of neuronal NF-κB have been identified, including calcium, inflammatory cytokines (i.e., tumor necrosis factor alpha), and the induction of experimental paradigms thought to reflect learning and memory at the cellular level (i.e., long-term potentiation). NF-κB is also activated after learning and memory formation in vivo. In turn, activation of NF-κB can elicit either suppression or activation of other genes. Studies are only beginning to elucidate the multitude of neuronal gene targets of NF-κB in the typical brain, but research to date has confirmed targets involved in a wide array of cellular processes, including cell signaling and growth, neurotransmission, redox signaling, and gene regulation. Further, several lines of research confirm dysregulation of NF-κB in Alzheimer’s disease (AD), a disorder characterized clinically by a profound deficit in the ability to form new memories. AD-related neuropathology includes the characteristic amyloid beta plaque formation and neurofibrillary tangles. Although such neuropathological findings have been hypothesized to contribute to memory deficits in AD, research has identified perturbations at the cellular and synaptic level that occur even prior to more gross pathologies, including transcriptional dysregulation. Indeed, synaptic disturbances appear to be a significant correlate of cognitive deficits in AD. Given the more recently identified role for NF-κB in memory and synaptic transmission in the typical brain, the expansive network of gene targets of NF-κB, and its dysregulation in AD, a thorough understanding of NF-κB-related signaling in AD is warranted and may have important implications for uncovering treatments for the disease. This review aims to provide a comprehensive view of our current understanding of the gene targets of this transcription factor in neurons in the intact brain and provide an overview of studies investigating NF-κB signaling, including its downstream targets, in the AD brain as a means of uncovering

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.