TABLE 2.
Summary of the expression change, molecular target, and significance of miRNAs differentially expressed in the CSF of AD patients.
| Name | Change | Target | Effect on translation and significance | ||
| miR-100-5p | ↑ | Wallach et al., 2021 | TLR7/8 mTOR |
Increased binding and activation of microglial TLR7/8 promotes autonomous neurodegeneration and cortical accumulation of microglia; Increased inhibition of PI3K/Akt/mTOR pathway in late-stage AD leads to increased neuronal apoptosis | Ye et al., 2015; Wallach et al., 2021 |
| miR-101-3p | ↑ | Sørensen et al., 2016; Zhou et al., 2019 | APP | Although upregulated in CSF, decreased brain levels cause loss of APP inhibition increasing Aβ deposition | Vilardo et al., 2010; Zhou et al., 2019; Lee et al., 2021 |
| miR-103 | ↓ | Denk et al., 2015 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Denk et al., 2015; Lee et al., 2021 |
| miR-106a | ↑ | Denk et al., 2015 | APP | Although upregulated in CSF, decreased brain levels cause loss of APP inhibition increasing Aβ deposition | Lee et al., 2021 |
| miR-10b-5p | ↑ | Sørensen et al., 2016 | HODX10 | Increased inhibition of HODX10 and subsequent activation of the Rho/ROCK signaling pathway mediates hippocampal neuronal injury and inflammation | Ruan et al., 2021 |
| miR-124-3p | ↓ | Burgos et al., 2014 | CAV1 | Decreased inhibition of Caveolin-1 and subsequent modulation of the PI3K/Akt/GSK-3b pathway promotes tau hyperphosphorylation, neurofibrillary tangle formation, and cellular apoptosis | Kang et al., 2017; Samadian et al., 2021 |
| miR-125b | ↑ | Galimberti et al., 2014 | ERK1/2 Bcl-W DUSP6 PPP1CA |
Increased activation of ERK1/2 and downregulation of tau phosphatases (Bcl-W, DUSP6, PPP1CA) promotes tau hyperphosphorylation and reduces neuronal cell viability | Banzhaf-Strathmann et al., 2014 |
| miR-125b-5p | ↓ | Sørensen et al., 2016; Liu et al., 2022 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Li et al., 2020 |
| miR-1273g-3p | ↑ | Kim et al., 2021 | BACE1 Nicastrin TIMM13 GLRX5 MTCH1 |
Increased activation of the JNK pathway upregulates BACE1 and Nicastrin expression inducing Aβ and ROS production; Increased inhibition of mitochondrial genes (TIMM13, GLRX5, MTCH1) results in mitochondrial dysfunction and BACE1 upregulation | Kim et al., 2021 |
| miR-130a-3p | ↓ | Sørensen et al., 2016 | DAPK1 | Decreased inhibition of DAPK1 promotes hippocampal neurotoxicity and is associated with worse cognitive decline | Wang et al., 2021 |
| miR-132 | ↑ | Denk et al., 2015 | GTDC-1 CDK5 SIRT1 |
Increased inhibition of GTDC-1 promotes tau hyperphosphorylation and neuronal apoptosis by upregulation of Bax and downregulation of BCL2; Increased stimulation of CDK5 promotes tau hyperphosphorylation; Increased SIRT1 inhibition promotes tau hyperphosphorylation and amyloidogenesis | Hernandez-Rapp et al., 2016; Liu and Zhang, 2019 |
| miR-140-5p | ↓ | Lusardi et al., 2017 | ADAM10 SOX2 |
Although downregulated in CSF, increased brain levels inhibit expression of SOX2 and ADAM10 promoting the intraneural accumulation of Aβ and progression of AD | Akhter et al., 2018 |
| miR-142-3p | ↓ | Lusardi et al., 2017 | MAPT | Decreased regulation of MAPT compromises oligodendrocyte differentiation and cortical myelination exacerbating neurodegeneration | Hinman et al., 2021 |
| miR-143-3p | ↑ | Sørensen et al., 2016 | NRG1 | Increased inhibition of BACE1-dependent cleavage of NRG1 reduces neuronal cell viability and is associated with worse cognitive decline | Sun et al., 2020 |
| miR-146a | ↓ | Kiko et al., 2014; Liu et al., 2022 | Nkd2 | Overexpression of miRNA-146a in vivo has been demonstrated to induce microglial polarization (M1 pro-inflammatory to M2 phagocytic) and inhibit NLRP3 inflammasome formation enhancing Aβ clearance and reducing neuroinflammation, respectively, but the exact mechanisms remain unknown | Liang et al., 2021 |
| miR-146a-5p | ↑ | Sørensen et al., 2016 | TIGAR | Increased inhibition of TIGAR decreases NADPH production and GSH formation facilitating ROS production and neuronal pyroptosis (caspase-1-dependent cell death) | Lei et al., 2021 |
| miR-150-5p | ↑ | Sørensen et al., 2016 | PDCD4 | Associated with lower global cognitive scores, higher CSF t-tau, lower CSF Aβ42 levels, and lower blood PDCD4 | Chia et al., 2022 |
| miR-15a-5p | ↓ | Liu et al., 2022 | ERK1 | Decreased inhibition of ERK1 promotes tau phosphorylation and AD progression | Hébert et al., 2010 |
| miR-15b | ↑ | Denk et al., 2015 | BACE1 | Although upregulated in CSF, decreased brain levels cause loss of BACE1 inhibition increasing Aβ deposition | Gong et al., 2017; Liu et al., 2022 |
| miR-16 | ↓ | Denk et al., 2015 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition at the early stages of AD | Zhong et al., 2018; Manna et al., 2020 |
| miR-16-5p | ↓ | Lusardi et al., 2017 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Zhang et al., 2020 |
| miR-193a-3p | ↓ | Lusardi et al., 2017 | PTEN | Decreased inhibition of PTEN facilitates the dysregulation of the PI3K/AKT cell survival signaling pathway leading to neuronal apoptosis and AD progression | Takalkar et al., 2016 |
| miR-195 | ↓ | Cao et al., 2021; Liu et al., 2022 | SYNJ1 MFN2 |
Decreased inhibition of SYNJ1 facilitates the cleavage of neuronal membrane filaments and is positively correlated with the patient’s MMSE score while negatively correlated with CSF tau levels; Co-downregulation of MFN2 proteins facilitates mitochondrial dysfunction by fusion-fission imbalance | Zhang R. et al., 2016; Cao et al., 2021 |
| miR-19b-3p | ↓ | Sørensen et al., 2016 | BACE1 STAT3 |
Decreased inhibition of BACE1 leads to increased Aβ deposition; Loss of downregulation of STAT3 phosphorylation and activation leads to reactive gliosis and poor cognitive function | Wu et al., 2017; Zhang et al., 2020 |
| miR-204-5p | ↑ | Sørensen et al., 2016 | TRPML1 | Increased inhibition of TRPML1 disrupts lysosomal storage/transport and is associated with dysregulation of autophagy, increased accumulation of intraneural Aβ, decreased mitophagy, and decreased ROS removal | Zhang L. et al., 2021 |
| miR-206 | ↑ | Sørensen et al., 2016 | BDNF IGF1 |
Increased inhibition of BDNF results in synaptic dysfunction and impaired memory consolidation; Increased inhibition of IGF1 compromises microglial-mediated Aβ clearance and promotes LPS-induced neuroinflammation | Lee et al., 2012; Xing et al., 2016 |
| miR-210 | ↓ | Liu et al., 2022 | VEGF | Decreased stimulation of VEGF is associated with AD progression | Zhu et al., 2015 |
| miR-22-3p | ↓ | Sørensen et al., 2016 | SOX9 MAPK14 |
Decreased inhibition of SOX9 and MAPK14 indirectly promotes Aβ deposition and neuronal apoptosis | Ji Q. et al., 2019; Xia et al., 2022 |
| miR-221-3p | ↑ | Sørensen et al., 2016 | ADAM10 | Increased inhibition of ADAM10 promotes intraneural accumulation of Aβ | Manzine et al., 2018 |
| miR-223-3p | ↓ | Lusardi et al., 2017 | NLRP3 | Decreased inhibition of the NLRP3 protein leads to inflammasome formation and sustained neuroinflammation in AD and is positively correlated to the MMSE score | Bauernfeind et al., 2012; Jia and Liu, 2016 |
| miR-23b-3p | ↓ | Sørensen et al., 2016 | Gnt-III GSK-3β |
Decreased inhibition of GnT-III facilitates APP cleavage by BACE1 promoting Aβ production; Decreased inhibition of GSK-3b facilitates tau hyperphosphorylation and ROS production | Pan et al., 2021; Jiang et al., 2022 |
| miR-26b | ↓ | Galimberti et al., 2014 | Rb1/E2F NEP |
Although downregulated in CSF, increased brain levels upregulate the expression of Rb1/E2F promoting neuronal apoptosis; increased downregulation of NEP increases Aβ aggregation and impairs memory | Absalon et al., 2013; Chu et al., 2018 |
| miR-27a-3p | ↓ | Sala Frigerio et al., 2013 | NEAT1 | Decreased inhibition of NEAT1 increases BACE1 activity and Aβ deposition which promotes the progression of AD but no correlation with MMSE/MOCA score exists yet | He et al., 2022 |
| miR-27b-3p | ↓ | Lusardi et al., 2017 | CCL2/CCR2 | Impairment of the chemokine/chemokine receptor axis in blood-derived monocytes (BDMs) results in decreased clearance of Aβ aggregates | Wang et al., 2019 |
| miR-29a | ↑ | Kiko et al., 2014; Müller et al., 2016 | BACE1 | Although upregulated in CSF, decreased brain levels cause loss of BACE1 inhibition increasing Aβ deposition and ROS production promoting neuronal loss | Hébert et al., 2008 |
| miR-29a-3p | ↑ | Lusardi et al., 2017 | NAV3 ZNF346 LIF |
Increased activation of NAV3, ZNF346, and LIF affects neuron regeneration, survival, and differentiation, respectively | Peña-Bautista et al., 2022 |
| miR-29b | ↑ | Kiko et al., 2014 | BACE1 | Although upregulated in CSF, decreased brain levels cause loss of BACE1 inhibition increasing Aβ deposition and ROS production promoting neuronal loss | Hébert et al., 2008 |
| miR-29b-3p | ↑ | Sørensen et al., 2016 | BCL2L2 MCL-1 |
Increased inhibition of anti-apoptotic factors BCL2L2 and MCL-1 promotes neuronal cell death | Lungu et al., 2013; Satoh et al., 2015 |
| miR-29c | ↓ | Denk et al., 2015 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Lei et al., 2015; Manna et al., 2020 |
| miR-29c-3p | ↓ | Sørensen et al., 2016 | BACE1 STAT3 |
Decreased inhibition of BACE1 leads to increased Aβ deposition; Loss of downregulation of STAT3 phosphorylation and activation leads to reactive gliosis and poor cognitive function | Wu et al., 2017 |
| miR-30a-5p | ↑ | Sørensen et al., 2016 | ADAM10 SIRT1 BDNF |
Increased SIRT1 inhibition promotes tau hyperphosphorylation and accelerates neuronal damage; Increased inhibition of ADAM10 promotes intraneural accumulation of Aβ; Increased inhibition of BDNF results in synaptic dysfunction and impaired memory consolidation | Croce et al., 2013; Sun et al., 2022 |
| miR-328-3p | ↓ | Tan et al., 2021; Liu et al., 2022 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Thangavelu et al., 2020; Lee et al., 2021 |
| miR-331-3p | ↓ | Lusardi et al., 2017 | SQSTM1 OPTN |
Although downregulated in early stage AD, this miRNA increases later on promoting Aβ plaque formation and impairing its autophagic clearance | Chen et al., 2021 |
| miR-335-5p | ↓ | Sørensen et al., 2016 | JNK3 | Decreased inhibition of the JNK3 signaling pathway results in increased Aβ deposition | Denk et al., 2015; Wang et al., 2020 |
| miR-340-5p | ↓ | Lusardi et al., 2017 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Liu et al., 2022 |
| miR-34a | ↑ | Denk et al., 2015; Liu et al., 2022 | NDUFC2 SHDC COX10 SIRT1 PTPA NR2A VAMP2 SYT1 ADAM10 |
Increased inhibition of electron transport chain complexes (NDUFC2, SHDC, COX10) compromises mitochondrial function and ATP formation leading to neuronal cell death; Increased SIRT1 and PTPA inhibition promotes tau hyperphosphorylation; Increased NR2A inhibition on post-synaptic membranes compromises synaptic plasticity impairing working memory; Increased VAMP2 and SYT1 inhibition on pre-synaptic membranes compromises vesicle exo/endocytosis; Increased inhibition of ADAM10 promotes intraneural accumulation of Aβ and rapid cognitive decline | Sarkar et al., 2016, 2019; Liu et al., 2022 |
| miR-361-5p | ↓ | Sørensen et al., 2016 | BACE1 | Decreased inhibition of BACE1 increases Aβ deposition and ROS production promoting neuronal loss | Ji Y. et al., 2019 |
| miR-373-5p | ↓ | Sørensen et al., 2016 | NLRP3 | Decreased inhibition of the NLRP3 protein leads to inflammasome formation and sustained neuroinflammation in AD | Taşdelen et al., 2022 |
| miR-374b-5p | ↑ | Sørensen et al., 2016 | BACE1 | Although upregulated in CSF, decreased brain levels cause loss of BACE1 inhibition increasing Aβ deposition | Liu et al., 2022 |
| miR-384 | ↓ | Liu et al., 2022 | APP BACE1 |
Decreased regulation of APP increases Aβ production; Loss of downregulation of BACE1 leads to increased Aβ deposition | Liu et al., 2014 |
| miR-423-5p | ↑ | Sørensen et al., 2016 | COX6A2 | Increased inhibition of COX6A2 dramatically decreases ATP production levels compromising cell survival and energy metabolism | Siengdee et al., 2015 |
| miR-433 | ↓ | Burgos et al., 2014 | JAK2/STAT3 | Decreased inhibition of the JAK2/STAT3 pathway allows for increased neuronal proliferation and apoptosis, reactive gliosis, synaptic dysfunction, and Aβ aggregation | Wang and Zhang, 2020; Liu et al., 2022 |
| miR-497-5p | ↓ | Sørensen et al., 2016 | Endophilin-1 | Decreased inhibition of Endophilin-1 allows for the sustained downregulation of tight junction proteins (ZO-1, occludin, claudin-5) increasing BBB permeability and contributing to AD neuroinflammation | Zhu et al., 2019 |
| miR-613 | ↑ | Liu et al., 2022 | BDNF | Increased inhibition of BDNF results in synaptic dysfunction and is associated with decreased hippocampal neuron survival and proliferation | Li et al., 2016 |
| miR-9-3p | ↑ | Sørensen et al., 2016 | Dmd SAP97 REST |
Modulates dendritic growth and synaptic plasticity of hippocampal neurons by targeting long-term potentiation genes (Dmd, SAP97) and the REST protein; Although initially upregulated, CSF miRNA-9-3p levels are reported to decrease with AD progression | Giusti et al., 2014; Sim et al., 2016 |
| miR-9-5p | ↓ | Burgos et al., 2014 | GSK-3β NRF2/KEAP1 |
Decreased inhibition of GSK-3b facilitates ROS production, mitochondrial dysfunction, and neuronal apoptosis; Decreased activation of NRF2/KEAP1 signaling pathways results in downregulation of antioxidant enzymes (HO-1, SOD-1, GCLC) | Yang et al., 2017; Liu et al., 2020 |
| miR-92a-3p | ↑ | Sørensen et al., 2016 | AMPARs | Decreased translation and incorporation of GluA1-containing AMPA receptors into the synaptic membranes of hippocampal neurons is associated with defective synaptic transmission and plasticity | Letellier et al., 2014 |
| miR-let-7i-5p | ↑ | Sørensen et al., 2016 | TLR4 | Increased activation of extracellular TLR4 contributes to widespread neuronal damage | Sørensen et al., 2016 |