MiRNAs that target amyloid precursor protein processing machinery in extracellular vesicles and particles derived from oral squamous cells carcinoma.

BACKGROUND: Considering that microRNAs (miRNAs), extracellular vesicles and particles (EVPs) and the amyloid precursor protein (APP) processing have been shown to be altered in oral squamous cells carcinoma (OSCC), it is possible that miRNAs that target APP processing pathways in EVPs are impacted in tumor cells. Our aim was to evaluate miRNAs that target APP itself or disintegrin and metalloproteinase domain 10 (ADAM10), which generate a trophic compound, sAPPα, in EVPs derived from OSCC cell lines, an aggressive and non-invasive, compared to normal keratinocytes. METHODS: We used two OSCC cell lines, an aggressive human oral squamous cell carcinoma cell line (SCC09) and a less aggressive cell line (CAL27) compared with a keratinocyte lineage (HaCaT). Cells were maintained in cell media, from which we isolated EVPs. EVPs were evaluated regarding their size and concentration using Nanotracking Analysis. We measured the levels of miRNAs which had as potential downstream target APP or ADAM10, specifically miR-20a-5p, miR-103a-3p, miR-424-5p, miR-92b-3p, miR-31-5p, and miR-93-5. RESULTS: There were no differences on size distributions and concentration of isolated EVPs. OSCC cell lines-derived EVPs miR-20a-5p, miR-92b-3p, and miR-93-5p were upregulated in comparison to HaCaT-derived EVPs; while miR-31-5p was reduced in EVPs obtained from CAL27 cells. CONCLUSION: Our results indicate changes in miRNAs that target APP machinery processing in EVPs derived from OSCC cell lines of different aggressiveness, which may be involved with abnormal miRNA expression in OSCC tissue and/or releasing tumor suppressor miRNA.

Exercise Modalities Improve Aversive Memory and Survival Rate in Aged Rats: Role of Hippocampal Epigenetic Modifications.

We aimed to investigate the effects of aging and different exercise modalities on aversive memory and epigenetic landscapes at brain-derived neurotrophic factor, cFos, and DNA methyltransferase 3 alpha (Bdnf, cFos, and Dnmt3a, respectively) gene promoters in hippocampus of rats. Specifically, active epigenetic histone markers (H3K9ac, H3K4me3, and H4K8ac) and a repressive mark (H3K9me2) were evaluated. Adult and aged male Wistar rats (2 and 22 months old) were subjected to aerobic, acrobatic, resistance, or combined exercise modalities for 20 min, 3 times a week, during 12 weeks. Aging per se altered histone modifications at the promoters of Bdnf, cFos, and Dnmt3a. All exercise modalities improved both survival rate and aversive memory performance in aged animals (n = 7-10). Exercise altered hippocampal epigenetic marks in an age- and modality-dependent manner (n = 4-5). Aerobic and resistance modalities attenuated age-induced effects on hippocampal Bdnf promoter H3K4me3. Besides, exercise modalities which improved memory performance in aged rats were able to modify H3K9ac or H3K4me3 at the cFos promoter, which could increase gene transcription. Our results highlight biological mechanisms which support the efficacy of all tested exercise modalities attenuating memory deficits induced by aging.

The amyloid precursor protein (APP) processing as a biological link between Alzheimer's disease and cancer.

Aging is a risk factor for several illnesses, such as Alzheimer's Disease and various cancers. However, an inverse correlation between malignancies and Alzheimer's Disease has been suggested. This review addressed the potential role of non-amyloidogenic and amyloidogenic pathways of amyloid precursor protein processing as a relevant biochemical mechanism to clarify this association. Amyloidogenic and non-amyloidogenic pathways have been related to Alzheimer's Disease and certain malignancies, respectively. Several known molecules involved in APP processing, including its regulation and final products, were summarized. Among them some candidate mechanisms emerged, such as extracellular-regulated kinase (Erk) and protein kinase C (PKC). Therefore, the imbalance of APP processing may be involved with the negative correlation between cancer and Alzheimer Disease.

The Aging Process Alters IL-1ß and CD63 Levels Differently in Extracellular Vesicles Obtained from the Plasma and Cerebrospinal Fluid.

OBJECTIVE(S): The aim of this study was to investigate exosomal markers and inflammatory cargo of extracellular vesicles (EVs) obtained from cerebrospinal fluid (CSF) and plasma in the aging process. We also studied the inflammatory cargo by quantifying IL-1ß levels. METHODS: Male Wistar rats, aged 3 and 21 months, were used (n = 12 in each group). The CSF and plasma of animals were collected, and isolation of EVs was performed using a commercial kit. Total protein concentration, acetylcholinesterase (AChE) activity, and CD63 and IL-1ß levels were evaluated. RESULTS: AChE activity in EVs increased in both samples, specifically in the circulating EVs and those in the CSF of the older group. An age-related increase was observed in CD63 levels in EVs from the CSF but a decrease was observed in plasma EVs of the older group. Student's t test showed that the young adult rats had significantly higher circulating IL-1ß levels in the EVs compared to the aged ones, without any effect on central content. CONCLUSION: Our data suggest that the normal aging process causes different changes in the profiles of central and circulating EVs. Altered IL-1ß levels in circulating EVs can be linked, at least partly, to age-related inflammatory conditions, and a disruption of the CFS exosomes in aged rats, evaluated by CD63 levels, can be related to susceptibility to neurodegenerative disorders.