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MicroRNAs (miRNAs) are short single-stranded RNA molecules that have a critical role in the regulation of gene expression. Alterations in miRNA expression levels have been observed in multiple tumor types and there is clear evidence on their active involvement in cancer development. Here, a comprehensive miRNA expression profiling in 16 pancreatic cancer cell lines and four normal pancreatic samples provided a specific molecular signature for pancreatic cancer and enabled us to identify 72 differentially expressed miRNAs with approximately half of them being up- and half downregulated in cancer cells as compared with normal samples. Of these, miR-31 was selected for further functional analyses based on its interesting "on-off" type expression profile, i.e., very low or even absent expression in normal pancreas and in six of the pancreatic cancer samples but extremely high expression in the remaining 10 cell lines. Quite unexpectedly, both the inhibition of miR-31 in AsPC-1 and HPAF-II pancreatic cancer cells with high endogenous expression and forced expression of miR-31 in MIA PaCa-2 with low endogenous levels led to reduced cell proliferation, migration, and invasion. More importantly, in AsPC-1 cells further enhancement of miR-31 also resulted in reduced cell migration and invasion, implicating that the level of miR-31 is critical for these phenotypes. This study highlights a specific miRNA expression pattern in pancreatic cancer and reveals that manipulation of miR-31 expression leads to reduced cell migration and invasion in pancreatic cancer.

An early symptom of Alzheimer’s disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore changes of early AD-associated pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.

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An early symptom of Alzheimer's disease (AD) is an impaired sense of smell, for which the molecular basis remains elusive. Here, we generated human olfactory neurosphere-derived (ONS) cells from people with AD and mild cognitive impairment (MCI), and performed global RNA sequencing to determine gene expression changes. ONS cells expressed markers of neuroglial differentiation, providing a unique cellular model to explore early AD-associated disease pathways. Our transcriptomics data from ONS cells revealed differentially expressed genes (DEGs) associated with cognitive processes in AD cells compared to MCI, or matched healthy controls (HC). A-Kinase Anchoring Protein 6 (AKAP6) was the most significantly altered gene in AD compared to both MCI and HC, and has been linked to cognitive function. The greatest change in gene expression of all DEGs occurred between AD and MCI. Gene pathway analysis revealed defects in multiple cellular processes with aging, intellectual deficiency and alternative splicing being the most significantly dysregulated in AD ONS cells. Our results demonstrate that ONS cells can provide a cellular model for AD that recapitulates disease-associated differences. We have revealed potential novel genes, including AKAP6 that may have a role in AD, particularly MCI to AD transition, and should be further examined.

Background The blood-brain barrier (BBB) has a major role in maintaining homeostasis of the brain. The primary function of the BBB is regulating the entry of molecules from the blood to the brain while protecting the brain from potentially harmful endogenous and exogenous substances. Transporters expressed in brain endothelial cells (BECs) mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs into the brain for the treatment of brain disorders including Alzheimer’s disease (AD). AD is the most common form of dementia, however, currently there is limited understanding of the role of BBB transporters in AD-related BBB dysfunction. Methods We investigated differences in BBB transporter expression and activity in brain endothelial-like cells (iBECs) differentiated from induced pluripotent stem cells (iPSCs) obtained from people carrying the familial AD Presenilin 1 (PSEN1) mutation (PSEN1 exon 9 deletion; AD-iBECs), healthy controls (Ctrl-iBECs), and isogenic PSEN1 exon 9-corrected lines (PSEN1COR-iBECs). We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound, in the absence (FUSonly) or presence of microbubbles (FUS+MB), to examine whether the expression or activity of key transporters can be modulated by therapeutic ultrasound, a novel technique allowing for transient BBB opening. Results Our results identified differences in the expression of BBB transporters between AD-iBECs and control iBECs, suggesting disease-specific effects on transporter expression. Additionally, our results demonstrated FUSonly and FUS+MB have the potential to modulate efflux transporter activity. Interestingly, AD-iBECs demonstrated significantly reduced PGP-mediated Aβ accumulation following FUS+MB, an effect not seen in Ctrl-iBECs, suggesting disease-related differences. Conclusions Our findings demonstrate that PSEN1 mutant AD-iBECs possess phenotypical differences compared to PSEN1 corrected and unrelated control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly and FUS+MB can modulate the BBB transporter expression and functional activity in iBECs, having potential implications on drug penetration and amyloid clearance. These findings highlight the differential responses of patient cells to FUS treatment, with patient-derived models likely providing an important tool for modelling of therapeutic effects of FUS.