MicroRNAs in Learning and Memory and Their Impact on Alzheimer’s Disease

Abstract

Learning and memory formation rely on the precise spatiotemporal regulation of gene expression, such as microRNA (miRNA)-associated silencing, to fine-tune gene expression for the induction and maintenance of synaptic plasticity. Much progress has been made in presenting direct evidence of miRNA regulation in learning and memory. Here, we summarize studies that have manipulated miRNA expression using various approaches in rodents, with changes in cognitive performance. Some of these are involved in well-known mechanisms, such as the CREB-dependent signaling pathway, and some of their roles are in fear- and stress-related disorders, particularly cognitive impairment. We also summarize extensive studies on miRNAs correlated with pathogenic tau and amyloid-β that drive the processes of Alzheimer’s disease (AD). Although altered miRNA profiles in human patients with AD and in mouse models have been well studied, little is known about their clinical applications and therapeutics. Studies on miRNAs as biomarkers still show inconsistencies, and more challenges need to be confronted in standardizing blood-based biomarkers for use in AD.

Lipopolysaccharides (LPSs) as Potent Neurotoxic Glycolipids in Alzheimer’s Disease (AD)

“…Early studies suggested that the identification and characterization of unique microbial signatures in neuropsychiatric diseases could provide new possibilities in targeted anti- or pro-biotic treatments [ 31 , 32 ]. However, HMP and parallel GI-tract microbiome studies involving multiple human populations and animal models of AD provided evidence indicating that due to wide variation in the microbial and genetic composition of individual GI-tract microbiomes even during healthy aging, it would be difficult to associate the abundance, speciation and/or complexity of any single microbial genus, species or classification with any single human disease [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 45 , 47 , 55 , 59 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ]. This is especially relevant to highly complex and heterogeneous neurological syndromes, such as AD, prion disease and other age-related neurodegenerative disorders, against their complex background of familial genetics, patient age, gender, drug history, age of onset and duration, inter-current disease and other critical environmental and lifestyle risk factors [ 61 , 62 , 63 , 70 ].…”

“…While commensal GI-tract microbes are beneficial and essential to human health, the enterotoxigenic forms of these same microorganisms have considerable potential to secrete highly neurotoxic biopolymers, including multiple varieties of Gram-negative bacterial-derived glycolipids such as LPSs, which are extremely potent inducers of pro-inflammatory and altered innate-immune and immunological signaling in infection, aging and diseases from AD to cancer [ 36 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. One major characterized pathogenic role of LPSs appears to be the stimulation of cytokine-, chemokine- and/or ROS-mediated pathological signaling programs that drive the induction of pro-inflammatory transcription factor NF-kB (p50/p65), which subsequently promotes the transcriptional up-regulation of NF-kB-sensitive microRNAs.…”

“…One major characterized pathogenic role of LPSs appears to be the stimulation of cytokine-, chemokine- and/or ROS-mediated pathological signaling programs that drive the induction of pro-inflammatory transcription factor NF-kB (p50/p65), which subsequently promotes the transcriptional up-regulation of NF-kB-sensitive microRNAs. These, in turn, target AD- or related-disease-associated mRNAs, which ultimately down-regulate critically pathologically relevant gene expression programs, resulting in the initiation, development and/or propagation of human disease [ 21 , 29 , 34 , 49 , 50 , 56 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 72 , 73 , 74 , 75 ]. For example, the LPS-mediated, ROS- and NF-kB-regulated up-regulation of microRNAs miRNA-30b, miRNA-146a and miRNA-155 in transgenic murine models of AD and in AD are now known to target and down-regulate the expression of important neuron-specific neurofilament and synaptic elements important in supporting and maintaining homeostasis in brain cells and neural signaling capabilities [ 51 , 52 , 57 , 58 , 59 , 60 , 71 ] ( Figure 2 ).…”

On the origin and nature of nongenetic information in eumetazoans

“…Vast evidence shows that miRNA expression patterns are regulated by neuronal activity 68,69,71,73,123,130–137 …”

Blood Analytes as Biomarkers of Mechanisms Involved in Alzheimer’s Disease Progression

“…Different technical approaches have been used to look for neurodegeneration-related specific blood biomarkers, such as those of proteomics [ 11 , 12 ] or miRNomics [ 13 , 14 ] or metabolomics [ 15 , 16 ], attempting to detect specific brain molecules —amyloid-beta (A ), tau and glial fibrillary acidic protein neurofilaments light chains [ 17 , 18 ]. On the other hand, fewer studies have been performed to assay non-specific blood analytes in patients with neurodegenerative illnesses [ 19 , 20 ], and more specifically AD [ 11 , 21 , 22 ] to find out novel interesting and useful correlations to brain biomarkers.…”