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.

Neurodegenerative disorders (NDD) have grabbed significant scientific consideration due to their fast increase in prevalence worldwide. The specific pathophysiology of the disease and the amazing changes in the brain that take place as it advances are still the top issues of contemporary research. Transcription factors play a decisive role in integrating various signal transduction pathways to ensure homeostasis. Disruptions in the regulation of transcription can result in various pathologies, including NDD. Numerous microRNAs and epigenetic transcription factors have emerged as candidates for determining the precise etiology of NDD. Consequently, understanding by what means transcription factors are regulated and how the deregulation of transcription factors contributes to neurological dysfunction is important to the therapeutic targeting of pathways that they modulate. RE1-silencing transcription factor (REST) also named neuron-restrictive silencer factor (NRSF) has been studied in the pathophysiology of NDD. REST was realized to be a part of a neuroprotective element with the ability to be tuned and influenced by numerous microRNAs, such as microRNAs 124, 132, and 9 implicated in NDD. This article looks at the role of REST and the influence of various microRNAs in controlling REST function in the progression of Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) disease. Furthermore, to therapeutically exploit the possibility of targeting various microRNAs, we bring forth an overview of drug-delivery systems to modulate the microRNAs regulating REST in NDD. Graphical abstract

In Alzheimer's disease (AD), neuroinflammation is detrimental in causing neurodegeneration. In the central nervous system, inhibitor of nuclear factor kappa B kinase subunit beta (IKK2/IKKβ/IKKB/IKBKB) signaling is linked to neuroinflammation-mediated learning and memory deficits through canonical pathway, while dopamine agonists have been known to reverse such effects. Our in silico analysis predicted if dopaminergic agonists could have IKKB inhibitory actions, to ameliorate neuroinflammation-associated learning and memory deficits. Here, the FDA-approved Zinc 15 database was screened with IKKB (PDB ID 4KIK). Potential molecules with IKKB inhibition were identified through docking, which also possessed dopaminergic activity. Molecular mechanics—generalized Born and surface area (MMGBSA), induced fit docking (IFD) and molecular dynamic (MD) studies of 100 ns simulation time were done. Apomorphine and rotigotine showed greater non-bonding and bonding interactions with amino acids of IKKB as compared to Aripiprazole in docking studies. The IFD studies predicted improved interactions with IKKB. MMGBSA scores indicated that the complex binding free energies were favorable, and MD studies showed an acceptable root mean square deviation between protein and ligands. The protein–ligand interactions showed hydrogen bonds, water and salt bridges necessary for IKKB inhibition, as well as solvent system stability. On the protein–ligand contact map, the varying color band intensities represented the ligand’s ability to bind with amino acids. Dopamine agonists apomorphine, rotigotine, and aripiprazole were predicted to bind and inhibit IKKB in in silico system. Graphical Abstract