RNA and Oxidative Stress in Alzheimer’s Disease: Focus on microRNAs

Table 3

Dysregulated microRNAs in association with both early-stage Alzheimer’s disease (AD) pathology and oxidative stress (OS).

miRNA	Up- or downregulated in brains with AD pathology	Target gene	Specific function and association with OS regulation clarified by cellular and animal experiments	Ref
miR-107	Downregulated in the temporal cortex at BraaK stages III/IV of MCI subjects	BACE1	MiR-107 decreases BACE-1 mRNA levels by binding to the 3 UTR of BACE1, hence decreases the production of Aβ.; OS served as the key trigger to downregulate miR-107 by cell-derived soluble Aβ.	[92, 115, 116]
miR-125b	Upregulated in the frontal cortex at BraaK stages III/IV of non-demented and early AD subjects	SPHK1; NCAM	Overexpression of miR-125b promotes APP and BACE1 expression and Aβ production and apoptosis by targeting SPHK1 through inflammation (via increase in TNF-α and IL-6) and OS (via decrease in SOD).; Mir-125b promotes tau phosphorylation by targeting NCAM.	[93, 99, 100]
miR-146a	Upregulated in the hippocampus at BraaK stages III/IV of preclinical or early AD subjects	CFH; ROCK1; SOD2	MiRNA-146a is NF-κB-sensitive and activates inflammation by targeting 3 UTR of CFH, an important repressor of the inflammatory response of the brain.; Overexpression of miR-146a induces tau phosphorylation by targeting ROCK1 via inhibition of PTEN.; Mir-146a is upregulated by ROS and downregulates SOD2 (mitochondrial manganese SOD).	[94, 101–103]
miR-200c	Upregulated in the hippocampus at BraaK stages III/IV of non-demented and early AD subjects.	PTEN; S6K1	In APP/PSEN1 double-transgenic mice, Aβ deposition results in ER stress that induces miR-200c.; MiR-200c supports cell survival and neurite outgrowth of cultured neuron by targeting PTEN.; MiR-200c reduces Aβ secretion by targeting S6K1 via reduction of IRS-1pSer and promoting insulin signaling.; MiR-200c is upregulated by ROS in primary hippocampal neuron.	[93, 111–113]
miR-210	Downregulated in the hippocampus at BraaK stages III/IV of non-demented and early AD subjects	ISCU1/2; COX10	Soluble Aβ leads to NMDAR overactivation, excessive calcium influx, mitochondrion-derived ROS production, and upregulation of miR-210.; MiR-210 targets ISCU1/2 and COX10 that have important roles in mitochondrial respiration and function	[93, 116]
miR-26b	Upregulated in the temporal cortex at BraaK stage III of patients with MCI	RB1	Overexpression of miR-26b leads to aberrant cell cycle re-entry and increased tau-phosphorylation by targeting RB1 via activation of RB1/E2F cell cycle and CDK5.; Sequence-specific inhibition of miR-26b in culture is neuroprotective against OS.	[95]
miR-30e	Upregulated in the hippocampus at BraaK stages III/IV of non-demented and early AD subjects	SNAI1	Overexpression of miR-30e increases the levels of SOD, GSH, and GSH-PX and decreases ROS levels by targeting SNAI1 through decreasing TGF-β and SMAD2 expression and increasing NOX4 expression.	[93, 110]
miR-34a	Upregulated in the frontal cortex and hippocampus at BraaK stages III/IV of non-demented and early AD subjects.	SIRT1; ADAM10; NMDAR 2B; TREM2; BCL2	Overexpression of miR-34a increases the levels of an adaptor protein p66shc and reduces tolerance to OS by targeting SIRT1.; Conditional miR-34a overexpression mouse shows cognitive impairment associated with accumulation of intracellular Aβ and tau hyperphosphorylation possibly through targeting ADAM10, NMDAR 2B, and SIRT1.; MiR-34a targets also the amyloid sensing- and clearance receptor protein TREM2 as well as anti-apoptotic protein BCL2.	[93, 104–108]
miR-34c	Upregulated in the hippocampus at BraaK stages III/IV of early AD subjects	SYT1	Overexpression of miR-34c mediates synaptic and memory deficits by targeting SYT1 through ROS generation, JNK activation, and p53 accumulation.	[94, 109]
miR-485	Downregulated in the frontal cortex at BraaK stage III of early AD subjects	BACE1; RAC1	MiR-485 decreases BACE1 mRNA levels by binding to BACE1 exon 6, hence decreases the production of Aβ.; MiR-485 upregulation alleviates ischemia-reperfusion injury by targeting RAC1 via NOTCH2 signaling, which are evidenced by improved cell viability, decreased OS markers, and reduced apoptotic rate.	[96, 118, 119]

3 UTR, three prime untranslated region; Aβ, amyloid-β; ADAM10, A Disintegrin and metalloproteinase domain-containing protein 10; APP, amyloid precursor protein; BACE1, β-site amyloid precursor protein-cleaving enzyme 1; BCL2, B-cell lymphoma 2; CDK5, cyclin-dependent kinase 5; CFH, complement factor H; COX10, cytochrome c oxidase assembly protein; ER, endoplasmic reticulum; GSH, glutathione; GSH-PX, glutathione-peroxidase; IL-6, interleukin-6; IRS-1pSer, insulin receptor substrate 1 at serine residues; ISCU1/2, iron-sulfur cluster scaffold homolog 1/2; JNK, Jun amino terminal kinase; MCI, mild cognitive impairment; NCAM, neural cell adhesion molecule; NF-κB, nuclear transcription factor κB; NMDAR, N-methyl-d-aspartate receptor; NOTCH2, neurogenic locus notch homolog protein 2; NOX4, NADPH oxidase 4; p66shc, 66 kDa proto-oncogene Src homologous-collagen homologue; PSEN1, presenilin-1; PTEN, phosphatase and tensin homolog; RAC1, RAS-related C3 botulinus toxin substrate 1; RB1, retinoblastoma 1; ROCK1, rho-associated, coiled-coil containing protein kinase 1; ROS, reactive oxygen species; S6K1, S6 kinase B1; SIRT1, silent mating type information regulation 2 homolog (sirtuin) 1; SMAD2, mothers against decapentaplegic homolog 2; SNAI1, snail family transcriptional repressor 1; SOD, superoxide dismutase; SPHK1, sphingosine kinase 1; SYT1, synaptotagmin 1; TGF, transforming growth factor; TNF-α, tumor necrosis factor-α; TREM2, triggering receptor expressed in myeloid cells 2.