Differential expression of MicroRNAs in Alzheimer’s disease: a systematic review and meta-analysis

Regulatory miRNAs in Cardiovascular and Alzheimer’s Disease: A Focus on Copper

“…A recent meta-analysis [ 101 ] highlighted the difficulties encountered when studying miRNAs in AD patients. Of about 1500 miRNAs extracted from different biological matrices (blood, CFS, MCI, and the brain), 56 miRNAs showing significant differential expression in AD compared with the healthy controls and 10 novel miRNAs were found in the blood, and 2 of them were downregulated: miR-103, which is involved in neurite transportation, and miR-107, which is involved in BACE1 regulation.…”

“…A recent meta-analysis showed that 40 miRNAs were significantly upregulated and 16 were downregulated in AD versus healthy controls. The analysis revealed that they were mainly involved in pathways related to apoptosis, immune response, and inflammation [ 101 ].…”

NF-kB (p50/p65)-Mediated Pro-Inflammatory microRNA (miRNA) Signaling in Alzheimer's Disease (AD)

“…AD places a tremendous socioeconomic burden on caregivers and on the healthcare system as a whole. Despite ~115 years of intense and directed research, no effective treatment or cure for AD exists, although many insights into the molecular-genetic nature of this age-related disease have been established (Alzheimer et al, 1995 ; Kaur et al, 2015 ; Lane et al, 2018 ; Dong et al, 2021 ; Hermans et al, 2021 ; Trejo-Lopez et al, 2021 ; Liu et al, 2022 ; Olufunmilayo and Holsinger, 2022 ; Pogue et al, 2022 ; Rastegar-Moghaddam et al, 2022 ; Singh et al, 2022 ; Tahami Monfared et al, 2022 ; Yoon et al, 2022 ). As a devastating, inflammatory, and terminal neurodegenerative disorder, one molecular genetic component that has emerged at the forefront of current AD research is the DNA-binding element NF-kB, probably the single most important transcription factor yet identified in the complex neuropathology of AD.…”

“…Exposure to these factors induces IkB decomposition triggered through a site-specific phosphorylation of an IκB kinase (IKK) complex, followed by degradation via the ubiquitin-proteasome system, and then rapid NF-kB-activated transcription by multiple pro-inflammatory NF-kB-sensitive gene promoters. The human brain and CNS contain a very active, pleiotropic NF-kB-signaling system that has a function in both neurological health and disease (Kaltschmidt and Kaltschmidt, 2009 ; Christian et al, 2016 ; Liu et al, 2022 ; Yoon et al, 2022 ). While the NF-kB (p50/p65; also known as p50/RelA) heterodimer is especially abundant in nervous tissues, other homo- or hetero-dimeric NF-kB transcription factor complexes containing at least 5 other molecular components that include RelA, RelB, c-Rel, p50, p52, and NFKB1 (p105) form at least 12 different identified NF-kB complexes.…”

“…All share the conserved Rel homology domain (RHD) responsible for DNA binding, dimerization, and association with the repressor protein IκB (Zhang et al, 2017 ; Pires et al, 2018 ; Baltimore, 2019 ; https://www.genecards.org/cgi-bin/carddisp.pl?gene=RELA ; last accessed 25 May 2022). It has been repeatedly demonstrated: (i) that activated NF-kB subsequently upregulates a select sub-group of disease-associated miRNAs comprising a well-characterized NF-kB-sensitive Homo sapiens- enriched family of potentially pathogenic miRNAs that include miRNA-9, miRNA-30b, miRNA-34a, miRNA-146a, and miRNA-155 normally involved in immunity, inflammation, and brain cell genetic function in the CNS (Lukiw, 2012 , 2020 ; Brennan et al, 2019 ; Juźwik et al, 2019 ; Barnabei et al, 2021 ; Song et al, 2021 ; Yoon et al, 2022 ); (ii) that the same miRNAs are upregulated in AD brain; (iii) that this group of significantly over-expressed miRNAs are abundant in progressive and often lethal viral and prion-mediated and/or related neurological syndromes associated with progressive inflammatory neurodegeneration; and (iv) that all of these NF-kB-sensitive endotoxin-responsive miRNA genes have as many as three tandem, functional NF-kB binding sites stacked in their immediate 5'-promoter region, making this miRNA gene family exceptionally sensitive to NF-kB activation and NF-kB-mediated transcriptional upregulation (Taganov et al, 2006 ; Lukiw et al, 2008 ; Alexandrov et al, 2019 ; Jauhari et al, 2020 ; Table 1 ). Interestingly, there is also abundant recent evidence (i) that endotoxins such as LPS and other biophysical-barrier-penetrating glycolipids and lipoproteins specifically induce neurodegeneration by promoting neuro-inflammatory signaling by stimulation of Toll-like receptors (TLRs) present on the outer membranes of glial cells of the CNS (Kumar, 2019 ; Singh et al, 2022 ); (ii) that extremely potent pro-inflammatory species of LPSs have been found by many independent groups to be localized in human brain neurons in AD brain (Zhan et al, 2018 , 2021 ; Alexandrov et al, 2019 ; Zhao et al, 2019a ; Singh et al, 2022 ); and (iii) that a life-long supply of microbiome-abundant Gram-negative bacteria-derived LPS would be available over the long-term to chronically upregulate NF-kB in the brain and CNS, as is observed in LPS-treated human neurons in primary culture and in AD temporal lobe neocortex, the latter an anatomical area targeted by the AD process (Lukiw and Bazan, 1998 ; Zhang et al, 2017 ; Zhan et al, 2018 , 2021 ; Zhao and Lukiw, 2018 ; Alexandrov et al, 2019 ; Zhao et al, 2019a ...…”