Nf-κb: A Target for Synchronizing the Functioning Nervous Tissue Progenitors of Different Types in Alzheimer's Disease

Abstract

Background: The efficacy of Alzheimer's disease (AD) treatment can be enhanced by developing neurogenesis regulation approaches by synchronizing regenerative-competent cell (RCCs) activity. As part of the implementation of this direction, the search for drug targets among intracellular signaling molecules is promising. Objective: This study aims to test the hypothesis that NF-кB inhibitors are able to synchronize the activities of different types RCCs in AD. Methods: The effects of NF-кB inhibitor JSH-23 on the functioning of neural stem cells (NSCs), neuronal-committed progenitors (NCPs), and neuroglial cells were studied. Individual populations of C57B1/6 mice brain cells were obtained by immunomagnetic separation. Studies were carried out under conditions of modeling β-amyloid-induced neurodegeneration (βAIN) in vitro. Results: We showed that β-amyloid (Aβ) causes divergent changes in the functioning of NSCs and NCPs. Also demonstrated that different populations of neuroglia respond differently to exposure to Aβ. These phenomena indicate a significant discoordination of the activities of various RCCs. We revealed an important role of NF-кB in the regulation of progenitor proliferation and differentiation and glial cell secretory function. It was found that the NF-кB inhibitor causes synchronization of the pro-regenerative activities of NSCs, NCPs, as well as oligodendrocytes and microglial cells in βAIN. Conclusion: The results show the promise of developing a novel approach to Alzheimer's disease treatment with NF-кВ inhibitors.

Effects of small molecules on neurogenesis: Neuronal proliferation and differentiation

“…It is known that inactivation of NF κ B and STAT3 leads to increased production of neurotrophins, including growth factors, by neuroglial cells 133 , 134 . Therefore, the coordinated activity of various compartments of the cell renewal system leads to the reconstruction of affected brain structures and the correction of locomotor activity and cognitive functions of the animals' CNS 135 .…”

MicroRNA (miRNA) Complexity in Alzheimer’s Disease (AD)

“… Legend to Table 2 —This recently updated table indicates the most abundant unique miRNA species ( n = 80) detected in the human brain hipppocampal CA1 region and includes miRNA expression levels complementary to data in previous reports [ 6 , 7 , 9 , 10 , 12 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]; importantly, miRNA species overlain in light gray (and their mRNA targets) have been strongly implicated in AD-relevant processes [ 9 , 32 , 33 , 34 , 35 , 36 ]; those miRNAs overlain with a darker shade of gray are further described in Figure 1 ; miRNAs with a single asterisk such as miRNA-7, miRNA-9, miRNA-30b, miRNA-34a, miRNA-125b, miRNA-146a, miRNA-155 and miRNA-450b are moderately abundant in controls; however, they increase several-fold in abundance in AD; many of these same miRNAs are implicated in other infectious, neuro-inflammatory, and/or immunological diseases including prion disease (PrD) [ 21 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]; miRNAs with two asterisks are among the most abundant miRNAs in this same region of the hippocampal CA1 region (see manuscript text); a superscript of ‘f’ denotes miRNAs known to be induced by the pro-inflammatory transcription factor NF-kB (p50/p65) complex [ 29 , 30 ...…”

“…Over the last ~16 years about ~2000 peer-reviewed research papers, including about ~600 review articles, have described the status of miRNA presence: (i) in AD-affected brain cells, tissues and biofluids compared to healthy age- and/or gender-matched controls; (ii) in human neuronal-glial (HNG) cells, mononuclear cells and other cell types in primary tissue culture stressed with cytokines (IL-1β, IL-6, TNFα), Aβ peptides, lipopolysaccharide (LPS), hypoxia and other AD-relevant stressors; and (iii) in transgenic murine models of AD (TgAD) such as the 5xFAD and other murine models into which specific AD-relevant genes have been inserted for the purpose of studying the mechanisms of their overexpression in the brain as these TgAD models age [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 52 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Many of these reports emphasize the finding of a single miRNA species significantly dysregulated in AD or in AD models and altered expression patterns in the transcriptome that are specifically targeted by a single abundance-modified miRNA.…”

C-Jun N-Terminal Kinases Inhibition: A New Approach to the Regulation of Venlafaxine Pharmacokinetics

“…The functioning of all cell types relies on the participation of the intracellular signal transduction system [1][2][3][4][5][6]. However, the specific roles of individual signal transduction pathways in regulating the xenobioticmetabolizing function of cells competent in this regard are largely unknown.…”