MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma

Sarkar, Sourav; Russell, Ashley E.; Engler-Chiurazzi, Elizabeth B.; Porter, Keyana N.; Simpkins, James W.

doi:10.14336/ad.2018.0409

Cited by 36 publications

(29 citation statements)

References 234 publications

(250 reference statements)

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“…This present work significantly advances the field. Specific miRNAs play a critical role in brain aging, neuroinflammation, neurodegeneration, and brain trauma [112] miRNAs play major roles in cognitive impairment in both AD-like pathology and dementia with Lewy bodies [113,114]. For example, miR-455-3p may have protective effects against abnormal APP processing and Aβ-toxicity in AD [115].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

et al. 2020

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Alzheimer's disease (AD) is the most common age-related form of dementia, associated with deposition of intracellular neuronal tangles consisting primarily of hyperphosphorylated microtubule-associated protein tau (p-tau) and extracellular plaques primarily comprising amyloid-β (Aβ) peptide. The p-tau tangle unit is a posttranslational modification of normal tau protein. Aβ is a neurotoxic peptide excised from the amyloid-β precursor protein (APP) by β-site APP-cleaving enzyme 1 (BACE1) and the γ-secretase complex. MicroRNAs (miRNAs) are short, single-stranded RNAs that modulate protein expression as part of the RNA-induced silencing complex (RISC). We identified miR-298 as a repressor of APP, BACE1, and the two primary forms of Aβ (Aβ40 and Aβ42) in a primary human cell culture model. Further, we discovered a novel effect of miR-298 on posttranslational levels of two specific tau moieties. Notably, miR-298 significantly reduced levels of 55 and 50 kDa forms of the tau protein without significant alterations of total tau or other forms. In vivo overexpression of human miR-298 resulted in nonsignificant reduction of APP, BACE1, and tau in mice. Moreover, we identified two miR-298 SNPs associated with higher cerebrospinal fluid (CSF) p-tau and lower CSF Aβ42 levels in a cohort of human AD patients. Finally, levels of miR-298 varied in postmortem human temporal lobe between AD patients and age-matched non-AD controls. Our results suggest that miR-298 may be a suitable target for AD therapy.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

et al. 2020

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“…Bioinformatic analyses indicated that these AD-associated genes are regulated by multiple TBI-associated miRNAs, notably miR-9 and miR-125, which are downregulated in chronic TBI; this suggests that these AD-associated genes are upregulated. Given evidence that TBI accelerates brain aging 27 , we found that at 24-96 h post-injury and as long as 32 years post-injury, miRNAs implicated in brain aging 28 are still found to be dysregulated. One positive finding is that the persistent upregulation of some miRNAs, such as miR-451, in chronic TBI is a sign of a restorative response; for example, increased levels of miR-451 via diet has been shown to protect cells from oxidative stress 29 .…”

Section: Discussionmentioning

confidence: 93%

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Weisz

Kennedy

Widen

et al. 2020

Sci Rep

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age-matched control serum. In these exploratory studies with rat and human tissues, we tested three hypotheses, 1) miRNA-seq profiles would identify TBI at all acute and chronic post-injury intervals, 2) miRNA-seq profiles would discriminate between focal and diffuse TBI and 3) serum miRNA-seq would reveal potential miRNA markers of neuropsychiatric and neurodegenerative sequelae. Methods Study design. The miRNA-seq and data analyses workflow is shown in Fig. 1A (rat studies) and Fig. 2A (human studies). Detailed methods, including rat surgical procedures, are described in Supplementary Materials and are summarized below. All procedures were done under a protocol (No. 1312056A) approved by the University of Texas Medical Branch at Galveston's Institutional Animal Care and Use Committee. All procedures performed as part of this study were performed in accordance with institutional, state, and U.S. federal guidelines and regulations. In the rat studies, for each post-injury interval, we sequenced four TBI and four sham-control hippocampi, thus 56 rats were used for miRNA-seq analysis. In the human studies, we sequenced 51 serum samples (six acute and six aged controls, 33 acute TBI representing 24, 48, 96 h post-injury, six chronic TBI [2-32 years post-injury]). Demographic characteristics are shown in Table 1. Rat hippocampus and serum isolation and PCR array analysis. Total RNA from rat hippocampal tissue was extracted and purified using Ribopure (Ambion) as in Boone and Weisz et al. 9. Serum from rats subjected to FPI and CCI was used for miRNA isolation and PCR array analysis as described in Supplementary Methods.

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“…Neuroinflammation is observed in many neurological disorders, including Alzheimer disease (AD), stroke, multiple sclerosis, Parkinson's disease (PD), and neuroinfections [1][2][3]. As innate immune cells in the central nervous system, microglia play a key role in regulating the pathogenesis of neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective and Anti—Neuroinflammatory Effects of a Poisonous Plant Croton tiglium Linn. Extract

Gupta

Park

Yang

et al. 2020

Toxins

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Neuroinflammation is involved in various neurological diseases. Activated microglia secrete many pro-inflammatory factors and induce neuronal cell death. Thus, the inhibition of excessive proinflammatory activity of microglia leads to a therapeutic effect that alleviates the progression of neuronal degeneration. In this study, we investigated the effect of Croton tiglium (C. tiglium) Linn. extract (CTE) on the production of pro- and anti-inflammatory mediators in microglia and astrocytes via RT-PCR, Western blot, and nitric oxide assay. Neurotoxicity was measured by cell viability assay and GFP image analysis. Phagocytosis of microglia was measured using fluorescent zymosan particles. CTE significantly inhibited the production of neurotoxic inflammatory factors, including nitric oxide and tumor necrosis factor-α. In addition, CTE increased the production of the neurotrophic factor, brain-derived neurotrophic factor, and the M2 phenotype of microglia. The culture medium retained after CTE treatment increased the survival of neurons, thereby indicating the neuroprotective effect of CTE. Our findings indicated that CTE inhibited pro-inflammatory response and increased the neuroprotective ability of microglia. In conclusion, although CTE is known to be a poisonous plant and listed on the FDA poisonous plant database, it can be used as a medicine if the amount is properly controlled. Our results suggested the potential benefits of CTE as a therapeutic agent for different neurodegenerative disorders involving neuroinflammation.

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MicroRNAs and the Genetic Nexus of Brain Aging, Neuroinflammation, Neurodegeneration, and Brain Trauma

Cited by 36 publications

References 234 publications

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

MicroRNA-298 reduces levels of human amyloid-β precursor protein (APP), β-site APP-converting enzyme 1 (BACE1) and specific tau protein moieties

MicroRNA sequencing of rat hippocampus and human biofluids identifies acute, chronic, focal and diffuse traumatic brain injuries

Neuroprotective and Anti—Neuroinflammatory Effects of a Poisonous Plant Croton tiglium Linn. Extract

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