NF-κB in Alzheimer's Disease: Friend or Foe? Opposite Functions in Neurons and Glial Cells

Abstract

Alzheimer's disease (AD) is a devasting neurodegenerative disease afflicting mainly glutamatergic neurons together with a massive neuroinflammation mediated by the transcription factor NF-κB. A 65%-plus increase in Alzheimer's patients by 2050 might be a major threat to society. Hallmarks of AD are neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau and amyloid beta (Aβ) plaques. Here, we review the potential involvement of transcription factor NF-κB by hereditary mutations of the tumor necrosis factor pathway in AD patients. One of the greatest genetic risk factors is APOE4. Recently, it was shown that the APOE4 allele functions as a null allele in human astrocytes not repressing NF-κB anymore. Moreover, NF-κB seems to be involved in the repair of DNA double-strand breaks during healthy learning and memory, a function blunted in AD. NF-κB could be a friend to healthy neurons by repressing apoptosis and necroptosis. But a loss of neuronal NF-κB and activation of glial NF-κB in AD makes it a foe of neuronal survival. Hopeful therapies include TNFR2 receptor bodies relieving the activation of glial NF-κB by TNFα.

Keywords: APOE4; Alzheimer’s disease; DNA breaks; DNA damage repair; NF-κB; TNF; glial cells; neuroinflammation; transcription factor.

Figure 1

(A) Overview of histopathological features leading to cortical atrophy of the gyri with enlarged sulcal spaces (depicted as Alzheimer’s brain). (B) Various neurological symptoms, including memory loss, are associated with disease progression.

Figure 2

Alzheimer’s disease is a major threat for society. (A) Data from Germany are plotted as number of cases and show a tremendous increase in AD for the next 30 years. (B) Major non-genetic risk factors and hereditary risk factors contribute to the development of AD.

Figure 3

Overview of neuroinflammation in AD and the impact of APOE4 on neurons and glial cells.

Figure 4

Overview of TNFR1-mediated activation of NF-κB dependent on linear ubiquitin. Membrane-bound TNF could be released by proteolytic cleavage mediated by ADAM17, resulting in intracellular signaling dependent on linear ubiquitin (small blue pearls). Activation of trimeric IKK complex could trigger nuclear localization of REL or RELA, which are controlled by feedback loops with IκBα or IκBε (modified from Sasaki et al., 2023 [53]). Alternatively, when ubiquitination of RIPK 1 is inhibited, interaction with FADD occurs, leading to activation of CASPASE-8-mediated cell death. In contrast, if CASPASE-8 is inhibited, RIPK3 interacts with MLKL, leading to necroptosis.

Figure 5

Summary of NF-κB function in healthy brain and AD. On the left side (in blue), the function of NF-κB in healthy neurons is depicted. Signaling through TNFR1 and 2 could lead to the expression of a neuroprotective gene program, inhibiting apoptosis as well as DNA repair. Glial cells do not contain activated NF-κB under healthy conditions. On the right side, NF-κB activity in AD is depicted (in red). Two main cell types are afflicted: neurons and glia. In contrast to healthy tissue, mainly TNFR1 is involved, without neuronal NF-κB activation, leading to neuronal death by necroptosis. In glial cells, a chronic inflammation is regulated by TNFR-mediated NF-κB activation, leading to high expression of proinflammatory cytokines TNF and IL-6. These could further exacerbate neuronal death.