The autophagy protein Def8 is altered in Alzheimer's disease and Aβ42-expressing Drosophila brains.

Alzheimer's disease (AD) is the most common neurodegenerative disorder, characterized by protein accumulation in the brain as a main neuropathological hallmark. Among them, Aβ42 peptides tend to aggregate and create oligomers and plaques. Macroautophagy, a form of autophagy characterized by a double-membrane vesicle, plays a crucial role in maintaining neuronal homeostasis by degrading protein aggregates and dysfunctional organelles as a quality control process.

Cancer History Avoids the Increase of Senescence Markers in Peripheral Cells of Amnestic Mild Cognitive Impaired Patients.

Epidemiological studies show that having a history of cancer protects from the development of Alzheimer's Disease (AD), and vice versa, AD protects from cancer. The mechanism of this mutual protection is unknown. We have reported that the peripheral blood mononuclear cells (PBMC) of amnestic cognitive impairment (aMCI) and Alzheimer's Disease (AD) patients have increased susceptibility to oxidative cell death compared to control subjects, and from the opposite standpoint a cancer history is associated with increased resistance to oxidative stress cell death in PBMCs, even in those subjects who have cancer history and aMCI (Ca + aMCI).

Long-term potentiation and spatial memory training stimulate the hippocampal expression of RyR2 calcium release channels.

Neuronal Ca signals generated through the activation of Ca-induced Ca release in response to activity-generated Ca influx play a significant role in hippocampal synaptic plasticity, spatial learning, and memory. We and others have previously reported that diverse stimulation protocols, or different memory-inducing procedures, enhance the expression of endoplasmic reticulum-resident Ca release channels in rat primary hippocampal neuronal cells or hippocampal tissue. Here, we report that induction of long-term potentiation (LTP) by Theta burst stimulation protocols of the CA3-CA1 hippocampal synapse increased the mRNA and protein levels of type-2 Ryanodine Receptor (RyR2) Ca release channels in rat hippocampal slices.

Senescence Markers in Peripheral Blood Mononuclear Cells in Amnestic Mild Cognitive Impairment and Alzheimer's Disease.

Recent studies suggest that cellular senescence plays a role in Alzheimer's Disease (AD) pathogenesis. We hypothesize that cellular senescence markers might be tracked in the peripheral tissues of AD patients. Senescence hallmarks, including altered metabolism, cell-cycle arrest, DNA damage response (DDR) and senescence secretory associated phenotype (SASP), were measured in peripheral blood mononuclear cells (PBMCs) of healthy controls (HC), amnestic mild cognitive impairment (aMCI) and AD patients.

Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells.

Filtering of Data-Driven Gene Regulatory Networks Using as a Case Study.

Gene Regulatory Networks (GRNs) allow the study of regulation of gene expression of whole genomes. Among the most relevant advantages of using networks to depict this key process, there is the visual representation of large amounts of information and the application of graph theory to generate new knowledge. Nonetheless, despite the many uses of GRNs, it is still difficult and expensive to assign Transcription Factors (TFs) to the regulation of specific genes.

DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer's Disease Patients, and a Transgenic Model of the Disease.

Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer's disease (AD). However, few studies are available concerning autophagy gene expression in AD patients.

Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheralblood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice.

Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort.

Background: Amyloid-β peptide (Aβ) deposition in Alzheimer's disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD.

Nicotinamide, a Poly [ADP-Ribose] Polymerase 1 (PARP-1) Inhibitor, as an Adjunctive Therapy for the Treatment of Alzheimer's Disease.

Nicotinamide (vitamin B3) is a key component in the cellular production of Nicotinamide Adenine Dinucleotide (NAD) and has long been associated with neuronal development, survival and death. Numerous data suggest that nicotinamide may offer therapeutic benefits in neurodegenerative disorders, including Alzheimer's Disease (AD). Beyond its effect in NAD stores, nicotinamide is an inhibitor of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme with multiple cellular functions, including regulation of cell death, energy/metabolism and inflammatory response.

Inverse Relationship Between Alzheimer's Disease and Cancer: How Immune Checkpoints Might Explain the Mechanisms Underlying Age-Related Diseases.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the adult population. There is evidence of an inverse epidemiological relationship between AD and cancer, another prevalent age-related disease. This has led to hypothesize that there could be a common biological mechanism, deregulated in opposite directions that might explain the phenomenon of mutual protection.

Calcium & ROS: Two orchestra directors for the requiem of death.

Tumor necrosis factor alpha (TNF) triggers regulated necrosis of mycobacterium-infected macrophages through of mitochondrial reactive oxygen species (mitoROS) production in a RIPK1/3-dependent manner. To explain that, Roca and colleagues describe an inter-orgallenar circuit which involves the lysosomal ceramide production, mitoROS, BAX activation and RyR Ca efflux from the endoplasmic reticulum into the mitochondrion.

Cancer Imprints an Increased PARP-1 and p53-Dependent Resistance to Oxidative Stress on Lymphocytes of Patients That Later Develop Alzheimer's Disease.

We have proposed that a common biological mechanism deregulated in opposite directions might explain the inverse epidemiological association observed between Alzheimer's disease (AD) and cancer. Accordingly, we showed that lymphocytes from AD patients have an increased susceptibility, whereas those from survivors of a skin cancer, an increased resistance to oxidative death induced by hydrogen peroxide (HO), compared to healthy controls (HC). We investigated the susceptibility to HO-induced death of lymphocytes in survivors of any type of cancer and in cancer survivors who later developed AD (Ca&AD).

Vitamin D Increases Aβ140 Plasma Levels and Protects Lymphocytes from Oxidative Death in Mild Cognitive Impairment Patients.

Background: Mild cognitive impairment (MCI) has an increased rate of progression to dementia. Alterations of some metabolic factors, such as deficiency of vitamin D, are a risk factor for cognitive deterioration. Vitamin D is involved in the clearance of β-amyloid (Aβ) from the brain.

PARP-1 and p53 Regulate the Increased Susceptibility to Oxidative Death of Lymphocytes from MCI and AD Patients.

Mild cognitive impairment (MCI) is a clinically detectable initial stage of cognitive deterioration with a high conversion rate to dementia. There is increasing evidence that some of the cerebral alterations present in Alzheimer type dementia can be found in peripheral tissues. We have previously shown that lymphocytes from Alzheimer's disease (AD) patients have increased susceptibility to hydrogen peroxide (HO)-induced death that depends on dementia severity.

RyR2-Mediated Ca Release and Mitochondrial ROS Generation Partake in the Synaptic Dysfunction Caused by Amyloid β Peptide Oligomers.

Amyloid β peptide oligomers (AβOs), toxic aggregates with pivotal roles in Alzheimer's disease, trigger persistent and low magnitude Ca signals in neurons. We reported previously that these Ca signals, which arise from Ca entry and subsequent amplification by Ca release through ryanodine receptor (RyR) channels, promote mitochondrial network fragmentation and reduce RyR2 expression. Here, we examined if AβOs, by inducing redox sensitive RyR-mediated Ca release, stimulate mitochondrial Ca-uptake, ROS generation and mitochondrial fragmentation, and also investigated the effects of the antioxidant -acetyl cysteine (NAC) and the mitochondrial antioxidant EUK-134 on AβOs-induced mitochondrial dysfunction.

Increased susceptibility to oxidative death of lymphocytes from Alzheimer patients correlates with dementia severity.

We previously reported on enhanced susceptibility to death of lymphocytes from Alzheimer's disease (AD) patients when exposed to hydrogen peroxide (H2O2)-induced oxidative stress and an increased resistance to death in those of patients with a history of skin cancer. This is consistent with our hypothesis proposing that the cellular machinery controlling cell death is deregulated in opposite directions in Alzheimer's disease (AD) and cancer, to explain the inverse association observed in epidemiological studies. Here we investigated whether the observed increased susceptibility correlates with the degree of dementia severity.

Ryanodine receptor-mediated Ca(2+) release underlies iron-induced mitochondrial fission and stimulates mitochondrial Ca(2+) uptake in primary hippocampal neurons.

Mounting evidence indicates that iron accumulation impairs brain function. We have reported previously that addition of sub-lethal concentrations of iron to primary hippocampal neurons produces Ca(2) (+) signals and promotes cytoplasmic generation of reactive oxygen species. These Ca(2) (+) signals, which emerge within seconds after iron addition, arise mostly from Ca(2) (+) release through the redox-sensitive ryanodine receptor (RyR) channels present in the endoplasmic reticulum.