MicroRNAs and MAPKs: Evidence of These Molecular Interactions in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder known to be the leading cause of dementia worldwide. Many microRNAs (miRNAs) were found deregulated in the brain or blood of AD patients, suggesting a possible key role in different stages of neurodegeneration. In particular, mitogen-activated protein kinases (MAPK) signaling can be impaired by miRNA dysregulation during AD. Indeed, the aberrant MAPK pathway may facilitate the development of amyloid-beta (Aβ) and Tau pathology, oxidative stress, neuroinflammation, and brain cell death. The aim of this review was to describe the molecular interactions between miRNAs and MAPKs during AD pathogenesis by selecting evidence from experimental AD models. Publications ranging from 2010 to 2023 were considered, based on PubMed and Web of Science databases. According to obtained data, several miRNA deregulations may regulate MAPK signaling in different stages of AD and conversely. Moreover, overexpressing or silencing miRNAs involved in MAPK regulation was seen to improve cognitive deficits in AD animal models. In particular, miR-132 is of particular interest due to its neuroprotective functions by inhibiting Aβ and Tau depositions, as well as oxidative stress, through ERK/MAPK1 signaling modulation. However, further investigations are required to confirm and implement these promising results.

Keywords: Alzheimer’s disease; MAPK; microRNAs; neurodegeneration.

Figure 1

The miRNA biogenesis process. RNA Pol II/III transcribed miRNA genes to form pri-miRNA transcript. Pri-miRNAs are processed by microprocessor complex Drosha–DGCR8 in the nucleus to generate pre-miRNAs. After translocation into the cytoplasm by exportin-5–Ran-GTP, pre-miRNAs are processed by RNase Dicer to form the mature miRNA duplex. Subsequently, one strand is degraded, while only one strand of the duplex is stably associated with RISC. The mature miRNA can interact with target mRNAs, containing partially complementary miRNA binding sites within the 3′UTR region, inducing translation repression, mRNA target cleavage, or mRNA deadenylation. The image was created using the image bank of Servier Medical Art (Available online: http://smart.servier.com/, accessed on 30 December 2022), licensed under a Creative Commons Attribution 3.0 Unported License (Available online: https://creativecommons.org/licenses/by/3.0/, accessed on 30 December 2022). RNA polymerase II or III: RNA Pol II/III; microRNA: miRNA; primary miRNA: pri-miRNA; ras-related nuclear protein: Ran; Guanosine-5′-triphosphate: GTP; precursor miRNA: pre-miRNA; RNA-induced silencing complex: RISC; messenger RNA: mRNA.

Figure 2

The MAPK signaling pathways. In mammalian cells, there are three well-known MAPK pathways: the ERK1/2, the c-JUN N-terminal kinase 1, 2, and 3 (JNK1/2/3), and the p38 α, β, δ, and γ MAPK pathways. ERK1/2 is activated in response to growth factors, hormones, and proinflammatory stimuli, while JNK1/2/3 and p38 α, β, δ, and γ are activated by cellular and environmental stresses, in addition to pro-inflammatory stimuli. The image was created using the image bank of Servier Medical Art (Available online: http://smart.servier.com/, accessed on 30 December 2022), licensed under a Creative Commons Attribution 3.0 Unported License (Available online: https://creativecommons.org/licenses/by/3.0/, accessed on 30 December 2022). Mitogen-activated protein kinases: MAPKs; c-Jun N-terminal kinase 1, 2, and 3: JNK1/2/3; extracellular signal-regulated kinases 1 and 2: ERK1/2; MAPK phosphatases 1, 3, 5, 7: MPK1/3/5/7; tumor necrosis factor receptor-associated factor: TRAF; SH2 containing protein tyrosine phosphatase-2: SHP2; Guanosine-5′-triphosphate: GTP; Rac Family Small GTPase 1: RAC1; MEK kinase 1: MEKK1; Apoptosis signal-regulating kinase 1: ASK1; transforming growth factor-β-activated kinase 1: TAK1; MAPK upstream kinase: MUK; MAP kinase kinase 3, 4, 6 and 7: MKK3/4/6/7; Thr-Gly-Tyr motif: TGY; Thr-Glu-Tyr motif: TEY; Thr–Pro–Tyr motif: TPY; receptor tyrosine kinase (RTK).

Figure 3

miRNAs and MAPKs interaction in Alzheimer’s disease. (a) The overexpression or the downregulation of miRNAs can act on p38 MAPK, JNK, and ERK in a direct or indirect way, exacerbating NFT and amyloid extracellular plaques in AD neurons. (b) Oxidative stress enhances miRNAs expression during AD, causing deregulation in the MAPK pathway and, consequently, synaptic and neuron loss. The overexpression of miR-132 decreases oxidative stress, p38 MAPK, and cognitive decline by targeting MAPK1. (c) The Aβ depositions induce ERK activation, which leads to a decrease in miR-34a expression levels and, thus, to neuronal death due to the CRNA. The overexpression of miR-590-5p and miR-326 plays an anti-apoptotic effect through indirect inhibition of p38 MAPK, ERK, and JNK activation. JNK mediates downstream miR-155 upregulation and promotes neuroinflammation during AD. The overexpression of miR-191-5p reduces microglia injury through the decrease in p38 MAPK and ERK activity by targeting the upstream MAP3K13 effector. Neuroinflammation plays an important role in the onset and progression of neurodegeneration and neuronal loss in neurodegenerative diseases. The image was created using the image bank of Servier Medical Art (Available online: http://smart.servier.com/, accessed on 30 December 2022), licensed under a Creative Commons Attribution 3.0 Unported License (Available online: https://creativecommons.org/licenses/by/3.0/, accessed on 30 December 2022). microRNAs: miRNAs; Mitogen-activated protein kinases: MAPKs; c-JUN N-terminal kinase: JNK; extracellular signal-regulated kinases: ERK; Neurofibrillary tangles: NFT; Alzheimer’s disease: AD; Mitogen-Activated Protein Kinase 1: MAPK1; reactive oxygen species: ROS; amyloid-β: Aβ; Transcription factor Jun: c-Jun; Mitogen-Activated Protein Kinase Kinase Kinase 12: MAP3K12; cell cycle-related neuronal apoptosis (CRNA).