Exosomal microRNAs in common mental disorders: Mechanisms, biomarker potential and therapeutic implications

Table 1 Summary of changes of exosomal microRNAs in Alzheimer's disease-related animal experiments

	miRNAs	Alteration	Model	Type tissue	Significance	Ref.
Intercellular communication	miR-135a	Increase	AD mouse models, human patients	CSF, serum, plasma	ATP-binding cassette transporter-A1 reduces the false negatives of exosomal miRNAs. Possible biomarker for AD	Liu et al[33]
	miR-193b	Increase	Cell models, AD mouse models, human patients	CSF, serum, cell	Possible biomarker for AD	Liu et al[55]
	miR-770-3p		AD mouse models	Brain tissue	As the downstream target of circ-Epc1, overexpression of circ-Epc1 affects M1 microglia and forms AD	Liu et al[56]
	miR-29	Decrease	AD rice models	Hippocampus	Exosomal miR-29 has protective effects on amyloid pathogenesis	Jahangard et al[57]
	miR-185-5p	Decrease	AD mouse models, AD cell models, human patients	Brain tissue, cell, serum and CSF	The expression of exosomal miR-185-5p was decreased by binding of APP 3’UTRs to miR-185-5p	Ding et al[58]
	miR-532-5p		AD mouse models	Brain tissue	The exosomal miR-532-5p targets EPHA4, and reduces EPHA4 its expression. Possible biomarker of AD	Liang et al[59]
	miR1385p		AD mouse models, cell models	Brain tissue, hippocampus, cell	By targeting Tau as a protective factor for AD. Possible therapeutic targets	Meng et al[60]
	miR-451a, miR-19a-3p		AD mouse models	Hippocampus	Possible biomarker for AD	Yan et al[61]
	miR-29b-2		Cell models	Cell	Reduces PSEN1 levels and inhibits secretory enzymes. Possible therapeutic targets	Lin et al[62]
	miR-196b-5p, miR-339-3p, miR-34a-5p, miR-376b-3p, miR-677-5p, miR-721		AD mouse models	Urine	Urinary exosomal miRNAs are promising to supplement or replace invasive cerebrospinal fluid. Possible biomarker for AD	Song et al[63]
Inflammatory response	miR-146a	Increase	AD mouse models	Hippocampus	Macrophage tolerance to TLR4 was induced	Yang et al[46]
	miR-124-3p		AD mouse models	Brain tissue	Neurodegeneration is mitigated by targeting Rela/ApoE signaling pathways to transfer into hippocampal neurons	Ge et al[64]
	miR-124	Increase	AD cell models	Cell	Regulation by the secretome miR-124-3p released through the AD cell models. A promising therapy in AD	Garcia et al[65]
	miR-21	Increase	AD mouse models	Brain tissue, hippocampus	Take part in immune processes. Possible biomarker for AD	Garcia et al[66]
	miR-146a-5p		AD mouse models, AD cell models	Cell, brain tissue, hippocampus, plasma	Targeted regulation of the HIF1α/mtROS pathway and improvement of NLRP3 inflammasome and inflammatory factors can alleviate cognitive impairment in IH mice	Zhang et al[67]
	miR-223		Cell models	Cell	Yb-1-mediated microglial exosomal sorting of miR-223 improves nerve cell damage repair and is a promising therapeutic target for AD	Wei et al[68]
	miR-223	Decrease	AD cell models	Cell	It acts as a protective factor for AD through the PI3K/Akt signaling pathway	Wei et al[47]
	miR-146a	Increase	AD mouse models	Hippocampus, CSF	Exosomal transfer of miR-146a is involved in the correction of cognitive dysfunction in AD	Nakano et al[69]
	miR-22		AD mouse models	CSF and peripheral blood	MiR-22-loaded ADMSC-derived exosomes can reduce the release of inflammatory cytokines by inhibiting pyroptosis	Zhai et al[48]
	miR-7670-3p		AD mouse models	Brain tissue	MiR-7700-3p reduces ATF6 expression, protects the integrity of dendritic spines in cortical and hippocampal neurons, and ultimately improves cognitive function	Chen et al[52]
Others	miR-124	Increase	AD cell models	Cell	A novel diagnostic biomarker in circulating exosomes is a potential therapeutic target for AD whenever its deregulation is determined	Garcia et al[70]
	miR-1306-5p	Decrease	Cell models, human patients	Cell, serum	CircAXL promotes the inhibition of PDE4A by targeting miR-1306-5p. Possible biomarker for AD	Meng et al[71]
	miR-211-5p		AD cell models	Cell	Inhibition of miR-211-5p may improve the efficacy of HUCMSC-derived exosomes in the treatment of AD by increasing the expression of NEP	Chen et al[72]

miRNA: MicroRNA; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; ATP: Adenosine triphosphate; APP: Amyloid precursor protein; 3’UTR: 3’untranslated region; NLRP3: NOD-like receptor thermal protein domain associated protein 3; TLR4: Toll-like receptor 4; HIF1α: Hypoxia inducible factor-1α; mtROS: Mitochondrial reactive oxygen species; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; ADMSC: Adipose derived mesenchymal stem cells; HUCMSC: Human umbilical cord mesenchymal stem cells; NEP: Neprilysin.

Table 2 Summary of changes of exosomal microRNAs in Alzheimer’s disease patients

miRNA	Alteration	Model	Type tissue	Significance	Ref.
miR-320a, miR-328-3p, miR-204-5p	Decrease	Human patients	CSF	Potential targets for miR-328-3p involve AMPK signaling pathways associated with amyloid and tau metabolism in AD. Reliable biomarkers of AD	Tan et al[73]
miR-455-3p	Increase	Human patients	CSF	A potential biomarker for AD	Kumar and Reddy[74]
miR-9, miR-21, miR29-b, miR-122, miR-132	Decrease	Human patients	Plasma	MiR-122 is related to alpha-tocopherol and may be a new targeted therapy	Boccardi et al[75]
miR-125b, miR-451a	Increase	Human patients	Peripheral blood	It plays a role through the PI3K/Akt signaling pathway. Possible biomarker for AD	Duan et al[76]
miR-342-5p	Increase	Human patients	Peripheral blood	Degradation of BACE1 mRNA in cells by targeting the 3’UTR sequence of BACE1 ameliorates β-Amyloid formation	Dong et al[77]
miR-16-5p, miR-25-3p, miR-92a-3p, miR-451a	Decrease	Human patients	Plasma	May have been involved in the early development of AD	Visconte et al[78]
miR-373, miR-204	Decrease	Human patients	Peripheral blood	Potential biomarkers for AD	Taşdelen et al[79]
miR-30b-5p, miR-22-3p, miR-378a-3p	Decrease	Human patients	Peripheral blood	Potential biomarkers for the diagnosis of AD	Dong et al[80]
miR-483-5p, miR-502-5p	Decrease	Human patients	Plasma	Possible biomarker for AD	Liu et al[81]
miR-29c-3p	Increase	Human patients	Plasma	Possible biomarker for AD	Li et al[82]
miR-23a	Increase	Human patients	Plasma	Possible biomarker for AD	Barbagallo et al[83]
miR-126-3p, miR-142-3p, miR-146a-5p, miR-223-3p	Decrease	Human patients	CSF and peripheral blood	As a biomarker reflecting AD severity	Aharon et al[84]
miR-384	Increase	Human patients	CSF and plasma	MiR-384 downregulates the expression and activity of ACE-1 to alleviate AD symptoms	Li et al[85]
miR-485-3p	Increase	Human patients	Saliva	Possible biomarker and treatment for AD	Ryu et al[86]
miR-486-3P	Increase	Human patients	Brain tissue and peripheral blood	Possible biomarker for AD	Cheng et al[87]
miR-185-5p		Human patients	Blood sample	Education decreased AD expression, depression increased AD expression, and participated in the production and accumulation of Aβ in patients, and enhanced depression, which participated in the production and accumulation of Aβ	Wang et al[88]

miRNA: MicroRNA; AD: Alzheimer’s disease; CSF: Cerebrospinal fluid; AMPK: Adenosine 5’-monophosphate-activated protein kinase; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; 3’UTR: 3’untranslated region.

Table 3 Summary of changes of exosomal microRNAs in schizophrenia related animal experiments

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-137	Increase	Gclm-KO mice, human patients	Plasma, prefrontal cortex	The changes in the level of miR-137/COX6A2 in plasma exosomes may be a marker of schizophrenia caused by PVI injury resulting from mitochondrial oxidative stress	Khadimallah et al[49]
miR-146a-5p	Increase	Schizophrenia mouse models, cell models	Plasma, cell	It may target NOTCH1, inhibit synaptic activity mediated by the Notch signaling pathway, and ultimately promote the occurrence and progression of schizophrenia in mice	Wang et al[89]
miR-223-3p	Increase	Mouse models, human postmortem brain, cell models	Cortical neuron, postmortem brain, astrocyte	miR-223 is a miRNA secreted by exosomes targeting glutamate receptors	Amoah et al[90]

miRNA: MicroRNA; PVI: Parvalbumin interneurons.

Table 4 Summary of changes of exosomal microRNAs in schizophrenia patients

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-203a-3p	Increase	Human patients, cells	Blood sample, cell	Targeted regulation of the 3’UTRs of DJ-1. Possible therapeutic target for schizophrenia	Tsoporis et al[91]
miR-675-3p		Human patients, cell models	Peripheral blood, cell	Associated with clozapine therapy. Understanding new pathogenesis	Funahashi et al[92]
miR-486-5p, miR-199a-3p, miR-144-5p, miR-451a, miR-143-3p, miR-142- 3p	Decrease	Human patients	Urine	Urinary exosomal miRNA is a biomarker for predicting schizophrenia	Tomita et al[93]

miRNA: MicroRNA; 3’UTR: 3’untranslated region.

Table 5 Summary of changes of exosomal microRNAs in major depressive disorder

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-146a, miR-155	Increase	Human patients	Blood sample	Interference by negative regulation of the TLR4 signaling pathway. It provides a potential diagnostic and therapeutic approach for MDD	Figueroa-Hall et al[96]
miR-21-5p, miR-145, miR-146a, miR-155	Decrease	Human patients	Serum	Exosomal miRNA may play an important role in predicting the response to antidepressant drugs	Hung et al[97]
miR-9-5p	Increase	MDD mouse models, MDD cell models	Serum, cell	It polarizes M1 of microglia, leading to further neuronal damage. Possible be a new therapeutic target for MDD	Hung et al[98]
miR-144-5p	Decrease	MDD mouse models	Hippocampus	Mediated by the PI3K/Akt/FoxO1 signaling pathway. A new potential therapeutic target	Xian et al[99]
miR-139-5p	Increase	MDD mouse models	Serum, hippocampus	It is activated during stress and mediates depression-like behavior in mice. A potential new approach to the diagnosis and treatment of MDD	Wei et al[39]
miR-139-5p	Decrease	Human patients	Serum	A promising biomarker for diagnosing MDD	Wu et al[100]
miR-186-5p	Decrease	MDD mouse models	Hippocampus	The exosome SERPINF1 in peripheral blood uses miR-186-5p as a potential therapeutic target for this disease	Liang et al[101]

miRNA: MicroRNA; MDD: Major depressive disorder; TLR4: Toll-like receptor 4; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B.

Table 6 Summary of changes of exosomal microRNAs in bipolar disorder

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-484, miR-652-3p, miR-142-3p	Decrease	BD human patients	Plasma	Abnormally regulated miRNAs enrich multiple target pathways, including the PI3K/Akt signaling pathway, fatty acid biosynthesis/metabolism, and extracellular matrix	Ceylan et al[103]
miR-185-5p	Increase	BD human patients	Plasma	Regulate the adhesion pathway	Ceylan et al[103]

miRNA: MicroRNA; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; BD: Bipolar disorder.

Table 7 Summary of changes of exosomal microRNAs in neurodevelopmental disorder

Disease	miRNAs	Alteration	Model	Type tissue	Significance	Ref.
ASD	miR-29b-3p	Increase	Mouse	Medial prefrontal cortex	Exosome-derived miR-29 b-3p negatively regulates IGF-1 in the mPFC	Chen et al[104]
	miR-21a-3p		ASD mouse models	Brian tissue	MiR-21a-3p/PI3K/Akt, as a signaling pathway, promotes neurogenesis and thus plays a regulatory role	Fu et al[105]
RTT	miR-21-5p		RTT mouse models	Brian tissue	Modulating the Epha4/TEK axis promotes early neurogenesis possible biomarker for RTT	Pan et al[40]

ASD: Autism spectrum disorder; RTT: Rett syndrome; miRNA: MicroRNA; PI3K: Phosphatidylinositol 3-kinase; Akt: Protein kinase B; IGF: Insulin like growth factor; mPFC: Medial prefrontal cortex.

Table 8 Summary of changes of exosomal microRNAs in post-traumatic stress disorder

miRNAs	Alteration	Model	Type tissue	Significance	Ref.
miR-15a-5p, miR-497a-5p, miR-511-5p	Decrease	PTSD mouse models	Hippocampus, medial prefrontal cortex	Brain region-dependent regulation of miRNAs targeting FKBP5, BDNF, and other stress-related genes	Maurel et al[106]
miR-326, miR-361, miR-767-5p		PTSD human patients	Plasma	Possible biomarker of PTSD	Devoto et al[107]
miR-139-5p	Decrease	PTSD human patients	Blood sample	MiR-139-5p was associated with the severity of PTSD symptoms in remote mTBI participants	Guedes et al[53]

mTBI: Mild traumatic brain injury; PTSD: Post-traumatic stress disorder; BDNF: Brain-derived neurotrophic factor; miRNA: MicroRNA.