Diverse and Composite Roles of miRNA in Non-Neuronal Cells and Neuronal Synapses in Alzheimer's Disease

Abstract

Neurons interact with astrocytes, microglia, and vascular cells. These interactions become unbalanced in disease states, resulting in damage to neurons and synapses, and contributing to cognitive impairment. Importantly, synaptic loss and synaptic dysfunction have been considered for years as a main pathological factor of cognitive impairment in Alzheimer's disease (AD). Recently, miRNAs have emerged as essential regulators of physiological and pathological processes in the brain. Focusing on the role of miRNAs in regulating synaptic functions, as well as different cell types in the brain, offers opportunities for the early prevention, diagnosis, and potential treatment of AD-related cognitive impairment. Here, we review the recent research conducted on miRNAs regulating astrocytes, microglia, cerebrovasculature, and synaptic functions in the context of AD-related cognitive impairment. We also review potential miRNA-related biomarkers and therapeutics, as well as emerging imaging technologies relevant for AD research.

Keywords: Alzheimer’s disease; astrocyte; cerebrovasculature; microRNA; microglia; synapse.

Figure 1

Interconnection of synapses and the cerebrovascular system. (a) A1 astrocytes cause a high production of Aβ by producing inflammatory factors, including IFN γ, IL-1β, TNF-α, IL-6, TGF-β, and massive amyloid precursor protein-cleaving enzymes, such as β-secretase (BACE1) and γ-secretase. (b) A2 astrocytes release neurotrophic factors, such BDNF, VEGF, and bFGF, which contribute to synaptic repair and neuroprotection. (c) Astrocytes secrete inflammatory factors, such as IL-1β and TNFα, to stimulate the production of ADEVs, carrying miR-125a-p and miR-16-5p to target NTKR3 to regulate synaptic stability. (d) Microglia alter the synaptic phenotypes in the hippocampal neuron by releasing a series of complement factors (e.g., C1q and C3), (e) inflammatory factors (e.g., IL-1α, TNF, and type-I IFN), and (f) extracellular vesicles (EVs) to deliver miR-146a-5p to target SYT1 and NLG1 to regulate synaptic density. (g) The cerebrovascular system is composed of endothelial cells, smooth muscle cells (SMCs), pericytes, perivascular immune cells (e.g., microglia), and surrounding astrocytes. Abnormal cerebral blood flow leads to a greater tendency for Aβ to be deposited within the basement membrane of blood vessels. (h) miR-126 in the endothelial cells participate in the regulation of cerebral blood flow. (i) miR-200b-3p, miR-200c-3p, and miR-205-5p considerably reduced low-density LRP1 in microvascular endothelial cells impairing Aβ clearance. (j) miR-126 and miR-145, specifically in brain capillaries, elevate pericyte coverage as well as promote endothelial cell activation. (k) Providing neurons with mitochondria-related energy chemicals, such as adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NAD+), creatine, or diazoxide are efficacious treatments that can effectively protect neurons from metabolic and Aβ-toxicity damage.