The Pivotal Role of NF-kB in the Pathogenesis and Therapeutics of Alzheimer's Disease

Abstract

Alzheimer's Disease (AD) is the most common neurodegenerative disease worldwide, with a high prevalence that is expected to double every 20 years. Besides the formation of Aβ plaques and neurofibrillary tangles, neuroinflammation is one the major phenotypes that worsens AD progression. Indeed, the nuclear factor-κB (NF-κB) is a well-established inflammatory transcription factor that fuels neurodegeneration. Thus, in this review, we provide an overview of the NF-κB role in the pathogenesis of AD, including its interaction with various molecular factors in AD mice models, neurons, and glial cells. Some of these cell types and molecules include reactive microglia and astrocytes, β-secretase, APOE, glutamate, miRNA, and tau protein, among others. Due to the multifactorial nature of AD development and the failure of many drugs designed to dampen AD progression, the pursuit of novel targets for AD therapeutics, including the NF-κB signaling pathway, is rising. Herein, we provide a synopsis of the drug development landscape for AD treatment, offering the perspective that NF-κB inhibitors may generate widespread interest in AD research in the future. Ultimately, the additional investigation of compounds and small molecules that target NF-κB signaling and the complete understanding of NF-κB mechanistic activation in different cell types will broaden and provide more therapeutic options for AD patients.

Keywords: Alzheimer’s; NF-κB; drug discovery; inflammation; neurodegeneration.

Figure 1

Amyloidogenic and non-amyloidogenic pathways. APP (center) can undergo proteolytic processing through two unique pathways, amyloidogenic processing (left) and non-amyloidogenic processing (right). In amyloidogenic processing, β-secretase cleaves APP, forming C99 and sAPPβ. C99 is further cleaved by γ-secretase to form amyloid beta peptides (Aβ). Importantly, the Aβ formation rate is dependent on the cleavage rate of APP by β-secretase. In non-amyloidogenic processing, APP is cleaved by α-secretase to form C83 and sAPPα, which can be further cleaved by γ-secretase, yielding p3 (adapted from [14]).

Figure 2

The central role of NF-κB in AD pathology. NF-κB facilitates the autocrine production of several factors that constitute AD pathology. NF-κB activates BACE1, which promotes Aβ fibril formation. Consequently, Aβ fibrils directly activate NF-κB, leading to the expression of APOE4, and mGluR5. In microglia and astrocytes. Aβ42 activates NF-κB, which induces the expression of proinflammatory factors that causes myelin injury. Additionally, NF-κB activates microRNA production which suppresses the expression of various neuroprotective factors. Similarly, the formation of hyperphosphorylated tau in AD brain is enhanced by NF-κB-dependent activation of SET, which inhibit tau’s dephosphorylation. Conversely, glycated tau triggers ROS production, leading to NF-κB activation. Collectively, the different pathways that contribute to neurodegeneration in AD are highly interconnected via continuous NF-κB activity in both neurons and glial cells.