The Role of microRNAs in Alzheimer’s Disease and Their Therapeutic Potentials

MicroRNAs (miRNAs) are short, endogenous, non-coding RNAs that post-transcriptionally regulate gene expression by base pairing with mRNA targets. Altered miRNA expression profiles have been observed in several diseases, including neurodegeneration. Multiple studies have reported altered expressions of miRNAs in the brains of individuals with Alzheimer’s disease (AD) as compared to those of healthy elderly adults. Some of the miRNAs found to be dysregulated in AD have been reported to correlate with neuropathological changes, including plaque and tangle accumulation, as well as altered expressions of species that are known to be involved in AD pathology. To examine the potentially pathogenic functions of several dysregulated miRNAs in AD, we review the current literature with a focus on the activities of ten miRNAs in biological pathways involved in AD pathogenesis. Comprehensive understandings of the expression profiles and activities of these miRNAs will illuminate their roles as potential therapeutic targets in AD brain and may lead to the discovery of breakthrough treatment strategies for AD

Suspension and transfer printing of ZnCdMgSe membranes from an InP substrate

Wide bandgap II-VI semiconductors, lattice-matched to InP substrates, show promise for use in novel, visible wavelength photonic devices; however, release layers for substrate removal are still under development. An under-etch method is reported which uses an InP substrate as an effective release layer for the epitaxial lift-off of lattice-matched ZnCdMgSe membranes. An array of 100-pm-square membranes is defined on a ZnCdMgSe surface using dry etching and suspended from the InP substrate using a three-step wet etch. The ZnCdMgSe membranes are transfer-printed onto a diamond heatspreader and have an RMS surface roughness < 2 nm over 400 |jm 2, similar to the epitaxial surface. Membranes on diamond show a photoluminescence peak at ∼520 nm and a thermal redshift of 4 nm with ∼3.6 MWm −2 continuous optical pumping at 447 nm. Effective strain management during the process is demonstrated by the absence of cracks or visible membrane bowing and the high brightness photoluminescence indicates a minimal non-radiative defect introduction. The methodology presented will enable the heterogeneous integration and miniaturization of II-VI membrane devices

3D Printed Quantum Dot Light-Emitting Diodes

Developing the ability to 3D print various classes of materials possessing distinct properties could enable the freeform generation of active electronics in unique functional, interwoven architectures. Achieving seamless integration of diverse materials with 3D printing is a significant challenge that requires overcoming discrepancies in material properties in addition to ensuring that all the materials are compatible with the 3D printing process. To date, 3D printing has been limited to specific plastics, passive conductors, and a few biological materials. Here, we show that diverse classes of materials can be 3D printed and fully integrated into device components with active properties. Specifically, we demonstrate the seamless interweaving of five different materials, including (1) emissive semiconducting inorganic nanoparticles, (2) an elastomeric matrix, (3) organic polymers as charge transport layers, (4) solid and liquid metal leads, and (5) a UV-adhesive transparent substrate layer. As a proof of concept for demonstrating the integrated functionality of these materials, we 3D printed quantum dot-based light-emitting diodes (QD-LEDs) that exhibit pure and tunable color emission properties. By further incorporating the 3D scanning of surface topologies, we demonstrate the ability to conformally print devices onto curvilinear surfaces, such as contact lenses. Finally, we show that novel architectures that are not easily accessed using standard microfabrication techniques can be constructed, by 3D printing a 2 × 2 × 2 cube of encapsulated LEDs, in which every component of the cube and electronics are 3D printed. Overall, these results suggest that 3D printing is more versatile than has been demonstrated to date and is capable of integrating many distinct classes of materials

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders

The endogenous incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) possess neurotrophic, neuroprotective, and anti-neuroinflammatory actions. The dipeptidyl peptidase 4 (DPP-4) inhibitor sitagliptin reduces degradation of endogenous GLP-1 and GIP, and, thereby, extends the circulation of these protective peptides. The current nonhuman primate (NHP) study evaluates whether human translational sitagliptin doses can elevate systemic and central nervous system (CNS) levels of GLP-1/GIP in naive, non-lesioned NHPs, in line with our prior rodent studies that demonstrated sitagliptin efficacy in preclinical models of Parkinson's disease (PD). PD is an age-associated neurodegenerative disorder whose current treatment is inadequate. Repositioning of the well-tolerated and efficacious diabetes drug sitagliptin provides a rapid approach to add to the therapeutic armamentarium for PD. The pharmacokinetics and pharmacodynamics of 3 oral sitagliptin doses (5, 20, and 100 mg/kg), equivalent to the routine clinical dose, a tolerated higher clinical dose and a maximal dose in monkey, were evaluated. Peak plasma sitagliptin levels were aligned both with prior reports in humans administered equivalent doses and with those in rodents demonstrating reduction of PD associated neurodegeneration. Although CNS uptake of sitagliptin was low (cerebrospinal fluid (CSF)/plasma ratio 0.01), both plasma and CSF concentrations of GLP-1/GIP were elevated in line with efficacy in prior rodent PD studies. Additional cellular studies evaluating human SH-SY5Y and primary rat ventral mesencephalic cultures challenged with 6-hydroxydopamine, established cellular models of PD, demonstrated that joint treatment with GLP-1 + GIP mitigated cell death, particularly when combined with DPP-4 inhibition to maintain incretin levels. In conclusion, this study provides a supportive translational step towards the clinical evaluation of sitagliptin in PD and other neurodegenerative disorders for which aging, similarly, is the greatest risk factor

Haptoglobin genotype and aneurysmal subarachnoid haemorrhage: individual patient data analysis

Objective:To perform an individual patient level data (IPLD) analysis and determine the relationship between haptoglobin (HP) genotype and outcomes after aneurysmal subarachnoid haemorrhage (aSAH).Methods:The primary outcome was favourable outcome on the modified Rankin Scale or Glasgow Outcome Score up to 12 months post-ictus. The secondary outcomes were occurrence of delayed ischemic neurological deficit, radiological infarction, angiographic vasospasm and transcranial Doppler evidence of vasospasm. World Federation of Neurological Surgeons scale, Fisher grade, age and aneurysmal treatment modality were covariates for both primary and secondary outcomes. As pre-planned, a two-stage IPLD analysis was conducted, followed by these sensitivity analyses: (1) unadjusted; (2) exclusion of unpublished studies; (3) all permutations of HP genotypes; (4) sliding dichotomy; (5) ordinal regression; (6) one-stage analysis; (7) exclusion of studies not in Hardy-Weinberg Equilibrium (HWE); (8) inclusion of studies without the essential covariates; (9) inclusion of additional covariates; (10) only including covariates significant in univariate analysis.Results:Eleven studies (five published, six unpublished), totalling 939 patients, were included. Overall the study population was in HWE. Follow-up times were 1, 3 and 6 months for 355, 516 and 438 patients. HP genotype was not associated with any primary or secondary outcome. No trends were observed. When taken through the same analysis higher age and WFNS were associated with an unfavourable outcome as expected.Conclusion:This comprehensive IPLD analysis, carefully controlling for covariates, refutes previous studies showing that HP1-1 associates with better outcome after aSAH

Additional Data for &quot;Haptoglobin genotype and aneurysmal subarachnoid haemorrhage: individual patient data analysis&quot;

This is the additional data for article &#39;Haptoglobin genotype and aneurysmal subarachnoid haemorrhage: individual patient data analysis&#39;.This supplemental data as original submitted is also available on request. Minor changes to the accompanying text were made between the two versions.</span

Cognitive Impairments Induced by Concussive Mild Traumatic Brain Injury in Mouse Are Ameliorated by Treatment with Phenserine via Multiple Non-Cholinergic and Cholinergic Mechanisms

<div><p>Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive substances (TBARS), a marker of oxidative stress. Phenserine counteracted this by augmenting homeostatic mechanisms to mitigate oxidative stress, including superoxide dismutase [SOD] 1 and 2, and glutathione peroxidase [GPx], the activity and protein levels of which were measured by specific assays. Microarray analysis of hippocampal gene expression established that large numbers of genes were exclusively regulated by each individual treatment with a substantial number of them co-regulated between groups. Molecular pathways associated with lipid peroxidation were found to be regulated by mTBI, and treatment of mTBI animals with phenserine effectively reversed injury-induced regulations in the ‘Blalock Alzheimer’s Disease Up’ pathway. Together these data suggest that multiple phenserine-associated actions underpin this compound’s ability to ameliorate cognitive deficits caused by mTBI, and support the further evaluation of the compound as a therapeutic for TBI.</p></div

Significantly regulated genes, Gene Ontologies and Canonical Pathways observed in hippocampal tissues from mTBI, mTBI/PHEN and PHEN animals are presented.

<p>Red arrows indicate up regulated genes, Green arrows indicate down regulated genes. <b>A:</b> Genes: by 14 days after injury, 50 and 129 genes were commonly up and down regulated, respectively, in the three treatment groups. The largest numbers of genes exclusively regulated were observed in the mTBI+PHEN treated animals, 332 genes and 528 genes were exclusively up and down regulated, respectively. Due to the large numbers of genes the identities and Z-ratios of the genes are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0156493#pone.0156493.s001" target="_blank">S1 Table</a>. <b>B:</b> Gene ontologies: ontologies derived from altered genes in hippocampal tissues indicate that 20 and 22 gene ontologies were commonly up and down regulated, respectively, in the three treatment groups. Several CNS or neuronal gene ontology listings are described in the results section; however, all ontology identities and Z-scores are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0156493#pone.0156493.s002" target="_blank">S2 Table</a>. <b>C:</b> Pathways: molecular pathways derived from altered genes in hippocampal tissues indicate no pathways were commonly regulated in the three treatment groups. Several pathways were CNS- or neuronal-related. These pathways are described in the results section. A list of pathways with corresponding Z-scores is provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0156493#pone.0156493.s003" target="_blank">S3 Table</a>.</p

Phenserine mitigates mTBI-induced impairments in visual and spatial memory.

<p>(<b>A</b>) mTBI mice demonstrate a deficit in visual memory compared with control (**p<0.01). Phenserine administration, at both doses utilized in this study significantly ameliorated behavioral deficits (##p<0.01). One-way ANOVA revealed a significant effect between groups [F(5,98) = 7.770, p = 0.000]. Fisher’s LSD post hoc analysis revealed that the preference index of the “mTBI” group was significantly lower than all other groups (**p<0.01). (<b>B</b>) mTBI mice demonstrate a significant deficit in spatial memory compared with control (**p<0.01). Phenserine administration significantly ameliorated this damage (<b>##</b>p<0.01 for 2.5mg/kg, and <b>#</b>p<0.05 for 5mg/kg). One-way ANOVA revealed a significant effect between groups [F(5,105) = 6.190, p = 0.000]. Fisher’s LSD post hoc analysis revealed that the preference index of the “mTBI” group was significantly lower than all other groups, other than “Phenserine only” 5 mg/kg (*p<0.05, **p<0.01).</p