Astrocytic MicroRNAs and Transcription Factors in Alzheimer's Disease and Therapeutic Interventions

Abstract

Astrocytes are important for maintaining cholesterol metabolism, glutamate uptake, and neurotransmission. Indeed, inflammatory processes and neurodegeneration contribute to the altered morphology, gene expression, and function of astrocytes. Astrocytes, in collaboration with numerous microRNAs, regulate brain cholesterol levels as well as glutamatergic and inflammatory signaling, all of which contribute to general brain homeostasis. Neural electrical activity, synaptic plasticity processes, learning, and memory are dependent on the astrocyte-neuron crosstalk. Here, we review the involvement of astrocytic microRNAs that potentially regulate cholesterol metabolism, glutamate uptake, and inflammation in Alzheimer's disease (AD). The interaction between astrocytic microRNAs and long non-coding RNA and transcription factors specific to astrocytes also contributes to the pathogenesis of AD. Thus, astrocytic microRNAs arise as a promising target, as AD conditions are a worldwide public health problem. This review examines novel therapeutic strategies to target astrocyte dysfunction in AD, such as lipid nanodiscs, engineered G protein-coupled receptors, extracellular vesicles, and nanoparticles.

Keywords: APOE4 nanodiscs; Astrocyte; Glutamate transporter 1; Transcriptional Factors; long non-coding RNA; microRNAs; neurodegenerative diseases; neuroinflammation.

Figure 1

Astrocyte-neuron crosstalk through miRs and APOE-mediated cholesterol regulation. Astrocytes communicate with nearby neurons by delivering miRs. The APOE-induced astrocyte (GREEN) releases miRs, and miR-126 suppresses the genes involved in the generation of neuronal cholesterol, which in turn causes acetyl-CoA accumulation in neurons. As a result, increased H3K27ac enrichment and histone acetylation at several IEG genes (VIOLET) cause enhanced memory consolidation. However, APOE4-induced astrocytes (PALE RED) cause miR-126 trafficking from astrocytes to neurons to considerably decrease, which in turn reduces the histone acetylation at the promoters of IEGs. Ultimately, it leads to decreased memory consolidation. Aged astrocytes (PALE BLACK) display greater miR-335-3p levels in astrocytes. However, miR-335-3p hampers both HMGCS1 and HMGCR, which results in reduced cholesterol production leading to AD. Additionally, neuronal miR-195 is markedly reduced by astrocyte-induced APOE4, which caused PIP2 levels to drop and SYNJ1 levels to rise. Higher levels of SYNJ1 are associated with enlarged endosomes and lysosomal defects, which impair the metabolism of cholesterol in neurons and lead to AD. This picture shows how dysregulation of cholesterol production in astrocytes affects AD modulation in both protective and pathogenic aspects. miRs: microRNAs; AD: Alzheimer’s disease; ApoE4: ApolipoproteinE4; Acetyl-CoA: Acetyl-coenzyme A; H3K27ac: Acetylation of lysine 27 on histone H3 protein subunit; IEG: Immediate early gene; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase-1; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; PIP2: Phosphatidylinositol 4,5-bisphosphate; SYNJ1: Synaptojanin 1.

Figure 2

Astrocytic microRNAs in glutamate uptake in Alzheimer’s disease.

Figure 3

Astrocytic microRNAs-long non-coding RNA interconnection in astrocytic inflammation Alzheimer’s disease. EVs released from the CP into the CSF during EE and treatment with BM-MSCs reach astrocytes, where both EE and BM-MSCs protect against Aβ and diabetes-induced astrocyte inflammation through the elevation of miR-146a and concurrent reduction in NF-κB. EVs produced by EE mainly work by inhibiting IRAK1 and TRAF6, which lower NF-κB. In Aβ-activated astrocytes, levels of c-Jun and miR-155 were both noticeably increased, which in turn inhibited SOCS-1. miR-155 levels are decreased by c-Jun silencing, which also protects against neuroinflammation-induced AD. miR-592 expression was increased and KIAA0319 levels were lowered in AD rat models, which further activated KEAP1 and inhibited NRF2 signaling, leading to an increase in NF-κB expression. Additionally, miR-592 suppression activates KEAP1/NRF2/ARE pathways, which in turn reduces neuroinflammation and astrocyte damage brought on by oxidative stress. Finally, after exposure to Aβ, lncRNA, SNHG14 was elevated and miR-223-3p levels were lowered. Astrocytic miR-223-3p directly targets NLRP3 and reduces miR-223-3p expression further activating the NLRP3 inflammasome, which leads to neuroinflammation and AD. miR-223-3p levels were significantly elevated, and AD was prevented by SNHG14 knockdown. Aβ: Amyloid beta; SOCS-1: Suppressor of cytokine signaling 1; CP: Choroid plexus; CSF: Cerebrospinal fluid; EE: Environmental enrichment; NF-κB: Nuclear factor-κB ; TRAF6: Tumor necrosis factor receptor-associated factor 6; IRAK1: Interleukin-1 receptor-associated kinase 1; BM-MSCs: Bone marrow mesenchymal stem cells; KEAP1: kelch-like ECH-associated protein 1; NRF2: Nuclear factor erythroid 2-related factor 2; ARE: Antioxidant response element; KIAA0319: Dyslexia-Associated Protein; lncRNAs: Long non-coding RNA; MEG3: Maternally expressed gene 3; NLRP3: NLR family pyrin domain containing 3; SNHG14: Small nucleolar RNA host gene 14.

Figure 4

Novel therapeutic strategies to target astrocyte dysfunction in Alzheimer’s disease. Reactive astrocytes are brought on by the administration of Aβ 1–42, and as a result, the levels of the ABCA1 transporter are lowered, inhibiting the release of cholesterol from astrocytes, and hence impeding cholesterol export. When APOA1 nanodiscs cross the BBB, they improve ABCA1 transporters, preventing the reduction of cholesterol efflux in astrocytes caused by exposure to Aβ 1-42. LPS disrupts the Gi-GPCR pathway, which in turn causes astrocytes to have significantly higher intracellular calcium levels and the accompanying neuroinflammation. Chemogenetic stimulation of the astrocytic Gi pathway by Gi- DREADD agonist CNO reduces intracellular calcium load in hippocampal astrocytes and concomitant neuroinflammation, which enhances synaptic transmission and prevents AD. MEM-PEG-PLGA nanoparticles, glucose-coated gold nanoparticles, RMP-7-Lf-QU-LS, and RA CNE can all cross the BBB and enter astrocytes to prevent Aβ-induced toxicity in neurons and astrocytes.GPCRs: G protein-coupled receptors; APOA-I: Apolipoprotein A-I; ABCA1:ATP-binding cassette transporter A1; NLP: Nanolipoprotein particle; DREADDs: Designer receptors only activated by designer drugs; CNO: Clozapine N-oxide; Gi: Inhibitory G protein; MEM-PEG-PLGA-NPs: Memantine–polyethylene glycol–Polylactic-co-glycolic nanoparticles; RMP-7-Lf-QU-LS: Quercetin (QU)-encapsulated liposomes(LS) grafted with RMP-7 and lactoferrin (Lf); RA CNE: Chitosan-coated rosmarinic acid nanoemulsions.