The underlying genetic variations of late-onset Alzheimer’s disease (LOAD) cases remain largely unknown. A combination of genetic variations with variable penetrance and lifetime epigenetic factors may converge on transcriptomic alterations that dri

Background. Alzheimer′s disease (AD) is a devastating neurological disorder and the main cause of dementia in the elderly population worldwide. Adult neurogenesis appears to be upregulated very early in AD pathogenesis in response to some specific aggregates of beta‐amyloid (Aβ) peptides, exhausting the neuronal stem cell pools in the brain. Previously, we characterized a conserved nonprotein‐coding antisense transcript for β‐secretase‐1 (BACE1), a critical enzyme in AD pathophysiology. We showed that the BACE1‐antisense transcript (BACE1‐AS) is markedly upregulated in brain samples from AD patients and promotes the stability of the (sense) BACE1 transcript. In the current paper, we examine the relationship between BACE1, BACE1‐AS, adult neurogenesis markers, and amyloid plaque formation in amyloid precursor protein (APP) transgenic mice (Tg‐19959) of various ages. Results. Consistent with previous publications in other APP overexpressing mouse models, we found adult neurogenesis markers to be noticeably upregulated in Tg‐19959 mice very early in the development of the disease. Knockdown of either one of BACE1 or BACE1‐AS transcripts by continuous infusion of locked nucleic acid‐ (LNA‐) modified siRNAs into the third ventricle over the period of two weeks caused concordant downregulation of both transcripts in Tg‐19959 mice. Downregulation of BACE1 mRNA was followed by reduction of BACE1 protein and insoluble Aβ. Modulation of BACE1 and BACE1‐AS transcripts also altered oligomeric Aβ aggregation pattern, which was in turn associated with an increase in neurogenesis markers at the RNA and protein level. Conclusion. We found alterations in the RNA and protein concentrations of several adult neurogenesis markers, as well as non‐protein‐coding BACE1‐AS transcripts, in parallel with the course of β‐amyloid synthesis and aggregation in the brain of Tg15999 mice. In addition, by knocking down BACE1 or BACE1‐AS (thereby reducing Aβ production and plaque deposition), we were able to modulate expression of these neurogenesis markers. Our findings suggest a distortion of adult neurogenesis that is associated with Aβ production very early in amyloid pathogenesis. We believe that these alterations, at the molecular level, could prove useful as novel therapeutic targets and/or as early biomarkers of AD.

Long non–protein coding RNAs (lncRNAs) are an important class of molecules that help orchestrate key cellular events. Although their functional roles in cells are not well understood, thousands of lncRNAs and a number of possible mechanisms by which they act have been reported. LncRNAs can exert their regulatory function in cells by interacting with epigenetic enzymes. In this study, we developed a tool to study lncRNA-protein interactions for high-throughput screening of small-molecule modulators using AlphaScreen technology. We tested the interaction of two lncRNAs: brain-derived neurotrophic factor antisense (BDNF-AS) and Hox transcript antisense RNA (HOTAIR), with Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase against a phytochemical library, to look for small-molecule inhibitors that can alter the expression of downstream target genes. We identified ellipticine, a compound that up-regulates BDNF transcription. Our study shows the feasibility of using high-throughput screening to identify modulators of lncRNA-protein interactions and paves the road for targeting lncRNAs that are dysregulated in human disorders using small-molecule therapies.

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by welldefined neuropathological brain changes including amyloid plaques, neurofibrillary tangles and the presence of chronic neuroinflammation. Objective: The brain penetrant BET bromodomain inhibitor JQ1 has been shown to regulate inflammation responses in vitro and in vivo, but its therapeutic potential in AD is currently unknown. Method: Three-month-old 3xTg mice were injected once a day with JQ1 (50 mg/kg) or vehicle for 15 weeks. At the end of the treatment learning and memory was assessed using the modified Barnes maze and the Y maze behavioral tests. Tissue from the brain and other organs was collected for molecular evaluation of neuroinflammation tau pathology and amyloid β. Results: JQ1 treatment reduced splenomegaly and neuroinflammation in the brain of treated mice where we observed a reduction in the expression of the pro-inflammatory modulators Il-1b, Il-6, Tnfa, Ccl2, Nos2 and Ptgs2. Additionally, JQ1-treated mice showed a reduction of tau phosphorylation at Ser396 in the hippocampus and frontal cortex while total levels of tau remained unaffected. On the other hand, JQ1 did not ameliorate learning and memory deficits in 7-month-old 3xTg mice. Conclusion: Taken together, our data suggest that BET bromodomain inhibitors hold the promise to be used for the treatment of neurological disorders characterized by neuroinflammation.

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the cardinal importance of rapid and accurate diagnostic assays. Since the early days of the outbreak, researchers with different scientific backgrounds across the globe have tried to fulfill the urgent need for such assays, with many assays having been approved and with others still undergoing clinical validation. Molecular diagnostic assays are a major group of tests used to diagnose COVID-19. Currently, the detection of SARS-CoV-2 RNA by reverse transcription polymerase chain reaction (RT-PCR) is the most widely used method. Other diagnostic molecular methods, including CRISPR-based assays, isothermal nucleic acid amplification methods, digital PCR, microarray assays, and next generation sequencing (NGS), are promising alternatives. In this review, we summarize the technical and clinical applications of the different COVID-19 molecular diagnostic assays and suggest directions for the implementation of such technologies in future infectious disease outbreaks.