Table 1.

A summary of microRNAs (miRNAs) linked to Alzheimer’s disease (AD).

miRNAs	Target mRNA	Models	Experimental Outcomes	Field of Application	Ref.
miRNA-101a-3p	APP	APP/ PSEN1 AD mice and SH-SY5Y cells	The overexpression of osthole-induced miRNA inhibits APP mRNA-101a-3p and reduces APP protein levels.	Therapeutic target	[40]
miRNA-200b/c	APP	Tg2576 mice; PMNCs and SH-SY5Y cells	miRNA-200b/c reduces Aβ secretion and Aβ-induced cognitive impairment. In addition, the transient transfection of neurons with miRNA-200b/c, decreased the secretion of Aβ in the conditioned medium.	Therapeutic targets	[43]
miRNA-200b; miRNA135a	APP; BACE1	APP/PSEN1 mice; primary neurons of the hippocampus mice, SH-SY5Y and HEK293 cells	miRNA-200b and miRNA-135a downregulated in hippocampi from APP/PS1 transgenic mice and repressed respectively the expression and activity of APP and BACE1.	Diagnostic markers	[44]
miRNA200a-3p	SIRT1	APP/PSEN1 AD mice and PC12 cells	Increased level of the miRNA-200a-3p and decreased level of SIRT1 in the hippocampus of APP/PS1 mice were observed. Downregulation of miRNA-200a-3p protected PC12 cells from Aβ25–35-induced neurotoxicity and inhibited the cell apoptosis. Moreover, SIRT1 was a target gene of miRNA-200a-3p and exerted a neuroprotective effect against Aβ25–35-induced toxicity in PC12 cell.	Therapeutic target	[45]
miRNA-29c	BACE1	SAMP8 and SAMR1 mice, primary hippocampal neurons of SAMR1 mice and peripheral blood of patients with AD	A decrease in miRNA-29c expression levels and a significant increase in BACE1 expression in peripheral blood samples from AD patients were recorded. miRNA-29c regulates BACE1 expression at the transcriptional level by directly targeting its 3’UTR. In SAMP8 mice miRNA-29c promoted a decrease in the production of Aβ by targeting BACE1.	Therapeutic target	[49]
miRNA-29c	NAV3	APP/PSEN1 AD mice and Neuro2A cells	miRNA-29c was significantly increased in the hippocampus of APP/PS1 mice, while it decreased in the frontal cortex. The differential expression of miRNA-29c in the hippocampus and frontal cortex of the APP/PS1 mouse brain was also accompanied by the inverse expression of the NAV3. In the in vitro study miRNA-29c directly mediated downregulation of NAV3 protein expression. miRNA-29c may influence neurodegenerative processes by targeting NAV3.	Therapeutic target	[50]
miRNA-137	CACNA1C	APP/PSEN1 AD mice and SH-SY5Y cells	The level of miRNA-137 decreased, while the level of CACNA1C increased in the hippocampus and cerebral cortex of AD mice. In SH-SY5Y cells inhibition of miRNA-137 also caused an increase in Ab1–42-induced hyperphosphorylation of TAU in SH-SY5Y cells.	Therapeutic target or diagnostic marker	[52]
miRNA-10a-5p, miRNA-142a-5p, miRNA-146a-5p, miRNA-155-5p, miRNA-211- 5p and miRNA-455-5p	-	APPtg and TAUtg mice	Upregulation between APPtg and TAUtg mice of miRNA-10a-5p, miRNA-142a-5p, miRNA-146a-5p, miRNA-155-5p, miRNA-211-5p, miRNA-455-5p; and upregulation of four of these (miRNA-142a-5p, miRNA-146a-5p, miRNA-155-5p, and miRNA-455-5p) also in AD patients.	Diagnostic markers	[57]
miRNA-330	VAV1	C57BL/6J AD mice and primary neuronal cells	Overexpression of miRNA-330 decreases expression of VAV1 via the MAPK pathway, reducing Aβ production, alleviates oxidative stress and mitochondrial dysfunction.	Therapeutic target	[58]
miRNA-34a	GRM7	3xTg-AD mice	Upregulated expression of miRNA-34a could be attributed to anxiety-like behaviors in 3xTg-Ad mice and linked to the downregulation of anxiety-related target gene GRM7.	Diagnostic markers	[68]
miRNA-34a	-	APP/PSEN1 and miRNA-34a KO/APP/PS1 mice	The level of miRNA-34a was increased, according to the increase in amyloid β (Aβ) in APP/PS1 mice; instead, in miRNA-34a knockout mice, a significantly reduced behavioral dysfunction was observed, mainly by inhibiting the γ-secretase activity.	Diagnostic markers	[63]
miRNA-34a	AMPA and NMDA	APP/PSEN1 and miRNA-34a KO/APP/PS1 mice	miRNA-34a deficiency promotes cognitive function by increasing synaptic plasticity via AMPA and NMDA receptors.	Diagnostic markers	[64]
miRNA-302/367	-	C57BL/6J AD mice	The miRNA-302/367 overexpression allows activated astrocytes to be converted into neurons by restoring some aspects of learning and memory deficits in an animal model of AD.	Therapeutic target	[71]
miRNA-125b, miRNA-181c, miRNA-9 and miRNA-191-5p	-	APP/PSEN1 AD mice and SH-SY5Y	Serum miRNA-125b, miRNA-191-5p, miRNA-9 were significantly downregulated and miRNA-28-3p was upregulated in APP/PS1 transgenic mice. Instead, the level of serum miRNA-125b, miRNA-9, and miRNA191-5p were upregulated in EGCG-treated APP/PS1.	Diagnostic markers	[74]
miRNA-139	CB2	SAMP8 and SAMR1 mice	miRNA139 expression was significantly higher in SAMP8 mice, compromising hippocampal-dependent learning and memory formation. In contrast, the downregulation of miRNA-139 in mice improved learning and memory in mice. Furthermore, miRNA-139, by inhibiting CB2 expression, decreases responses to pro-inflammatory stimuli and acts as a regulatory factor in the pathogenesis of AD.	Therapeutic target	[78]
miRNA-188-5p	-	5xFAD mice AD model, primary hippocampal neuron cells and human AD brains	The expression of miRNA-188-5p was downregulated in brain tissues from patients with AD and 5XFAD mice. Treatment with oligomeric Aβ1–42 decreased miRNA-188-5p expression in primary cultures of hippocampal neurons. On the contrary, miRNA-188-5p overexpression could alleviate the decrease in dendritic spine density in primary hippocampal neurons exposed to Aβ. Therefore, replenishment of mi-R188-5p restores the synaptic and cognitive deficits.	Diagnostic marker and therapeutic target	[82]
miRNA-132	ITPKB	APP/PSEN1 AD mice	MiRNA-132 loss aggravates amyloid and TAU pathology in AD brain via ITPKB upregulation in AD mice model. This lead to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. Downregulation of miRNA132 and upregulation of ITPKB was confirmed in human AD patients.	Diagnostic marker and therapeutic target	[85]
miRNA-132/212	TAU	3xTG-AD mice and mouse Neuro2a cells	Deletion of miRNA-132/212 caused abnormal TAU metabolism, accentuate TAU hyperphosphorylation and TAU aggregation. TAU is a direct target of miRNA-132. On the contrary, the treatment of 3xTg-AD mice with miRNA-132 mimics improved a long-term memory deficit and was determinate a significant reduction of phosphorylated TAU.	Therapeutic target	[88]
miRNA-132/212	SIRT1	3xTG-AD mice and mouse Neuro2a cells	Genetic deletion of miRNA-132/212 promotes Aβ production and amyloid plaque formation. SIRT1, MAPK1 / ERK2, and TAU were interesting miRNA-132 targets identified that were found to be upregulated in 3xTg-AD mice compared to controls. In contrast, all these genes were downregulated in Neuro2a132 cells. In addition, the modulation of miRNA-132 or SIRT1 can directly regulate Aβ production in cells.	Therapeutic target	[91]
miRNA-181	SIRT1 and c-Fos	3xTG-AD mice and SH-SY5Y cells	Compared to twelve-month wild type mice in the hippocampus of age-matched 3xTg-AD mice with plaques and tangles was found a significant upregulation of miRNA-181. Analysis of predicted targets of miRNA-181 identified c-Fos and SIRT-1. Both c-Fos and SIRT-1 levels were significantly decreased in the ventral hippocampus of twelve-month old 3xTg-AD mice. In addition, overexpression of miRNA-181 in SH-SY5Y cells significantly decreased c-Fos and SIRT-1.	Diagnostic marker and therapeutic target	[94]
miRNA-181c	CRMP-2	SAMP8 and SAMR1 mice; HT-22 and HEK293A cells	A significant decrease in miRNA-181c in the hippocampus of SAMP8 was recorded. miRNA-181c overexpression affects the 3’-UTR region of CRMP2. In HT-22 hippocampal neuronal cells, the overexpression of miRNA-181c downregulates the abundance of CRMP2 proteins at the post-transcriptional level.	Diagnostic marker	[96]
miRNA-206	BDNF	APP/PSEN1 mice and primary neuron cells from embryonic APP/PSEN1 mice hippocampus	miRNA-206 was upregulated, this overexpression resulted in a downregulated expression of BDNF that protects against cell death.	Diagnostic marker	[99]
miRNA-214-3p	ATG12	SAMR1 and SAMP8 mice; primary neuron cells from embryonic SAMP8 mice hippocampus and SH-SY5Y cells	Downregulated miRNA-214-3p was observed in hippocampal neurons of SAMP8 mice and also in cerebrospinal fluid from patients with SAD. miRNA-214-3p overexpression in primary neurons from SAMP8 mice inhibited autophagy. In contrast, antagomiRNA-214-3p promoted macroautophagy and apoptosis in SAMP8 mice neurons. miRNA-214-3p by directly targeting ATG12 inhibits the macroautophagy. In addition, the injection of miRNA-214-3p into the hippocampal improved the cognitive capacity of SAMP8 mice.	Therapeutic target	[106]
miRNA-146-a	ROCK1	5xFAD mice and SH-SY5Y cells	High levels of miRNANA-146a in neurons negatively regulate the translation of the ROCK1 protein. Reduction of neuronal protein ROCK1 leads to a reduction in the neuronal phosphorylation of PTEN resulting in the impaired dephosphorylation of neuronal TAU.	Diagnostic marker and therapeutic target	[92]
miRNA-574	NRN1	APP/PSEN1 mice; primary hippocampal neuron from the wild type and APP/PS1 transgenic mice and HT22 hippocampal neuronal cells	miRNA-574 was significantly increased in the hippocampus of 5-month APP/PS1 mice, showing synaptic loss and cognitive impairment. Bioinformatic analysis predicted that mRNA-574 targets the mRNA of Nrn1. In fact, in the in vitro study, miRNA-574 overexpression reduced NRN1 expression levels. In contrast, miRNA-574 suppression by the miRNA-574 inhibitor resulted in elevated levels of NRN1 expression.	Diagnostic marker and therapeutic target	[107]
miRNA-222	P27KIP1	APP/PSEN1 mice, SH-SY5Y and HEK-293T	Downregulation expression of miRNA-222 influences cell cycle dysregulation in AD, by targeting P27KIP1	-	[110]
miRNA-128	PPARγ	3xTG-AD mice and Neuro2A cells	The expression of miRNA-128 was upregulated, on the contrary, the expression of PPARγ was downregulated in the cerebral cortex of AD mice. Furthermore, PPARγ was a target of miRNA-128. In addition, the upregulation of miRNA-128 or the upregulation of PPARγ inhibited type AD performance, the formation of amyloid plaques, the generation of Aβ, the amyloidogenic processing of APP, and the inflammatory responses in AD mice. Instead, the inhibition of PPARγ improves the effects caused by miRNA-128.	Diagnostic marker and therapeutic target	[114]