Patient-Derived Fibroblasts With Presenilin-1 Mutations, That Model Aspects of Alzheimer's Disease Pathology, Constitute a Potential Object for Early Diagnosis.

Alzheimer's disease (AD), a neurodegenerative disorder that can occur in middle or old age, is characterized by memory loss, a continuous decline in thinking, behavioral and social skills that affect the ability of an individual to function independently. It is divided into sporadic and familial subtypes. Early-onset familial AD (FAD) is linked to mutations in genes coding for the amyloid-ß protein precursor (AßPP), presenilin 1 (PS1), and presenilin 2 (PS2), which lead to alterations in AßPP processing, generation of the Amyloid-ß peptide and hyperphosphorylation of tau protein. Identification of early biomarkers for AD diagnosis represents a challenge, and it has been suggested that molecular changes in neurodegenerative pathways identified in the brain of AD patients can be detected in peripheral non-neural cells derived from familial or sporadic AD patients. In the present study, we determined the protein expression, the proteomic and in silico characterization of skin fibroblasts from FAD patients with PS1 mutations (M146L or A246E) or from healthy individuals. Our results shown that fibroblasts from AD patients had increased expression of the autophagy markers LC3II, LAMP2 and Cathepsin D, a significant increase in total GSK3, phosphorylated ERK1/2 (Thr202/Tyr204) and phosphorylated tau (Thr231, Ser396, and Ser404), but no difference in the phosphorylation of Akt (Ser473) or the α (Ser21) and ß (Ser9) GSK3 isoforms, highlighting the relevant role of abnormal protein post-translational modifications in age-related neurodegenerative diseases, such as AD. Both 2-DE gels and mass spectrometry showed significant differences in the expression of the signaling pathways associated with protein folding and the autophagic pathway mediated by chaperones with the expression of HSPA5, HSPE1, HSPD1, HSP90AA1, and HSPE1 and reticular stress in the FAD samples. Furthermore, expression of the heat shock proteins HSP90 and HSP70 was significantly higher in the cells from AD patients as confirmed by Western blot. Taken together our results indicate that fibroblasts from patients with FAD-PS1 present alterations in signaling pathways related to cellular stress, autophagy, lysosomes, and tau phosphorylation. Fibroblasts can therefore be useful in modeling pathways related to neurodegeneration, as well as for the identification of early AD biomarkers.

Biomarker Candidates for Alzheimer's Disease Unraveled through In Silico Differential Gene Expression Analysis.

Alzheimer's disease (AD) is neurodegeneration that accounts for 60-70% of dementia cases. Symptoms begin with mild memory difficulties and evolve towards cognitive impairment. The underlying risk factors remain primarily unclear for this heterogeneous disorder. Bioinformatics is a relevant research tool that allows for identifying several pathways related to AD. Open-access databases of RNA microarrays from the peripheral blood and brain of AD patients were analyzed after background correction and data normalization; the Limma package was used for differential expression analysis (DEA) through statistical R programming language. Data were corrected with the Benjamini and Hochberg approach, and genes with p-values equal to or less than 0.05 were considered to be significant. The direction of the change in gene expression was determined by its variation in the log2-fold change between healthy controls and patients. We performed the functional enrichment analysis of GO using goana and topGO-Limma. The functional enrichment analysis of DEGs showed upregulated (UR) pathways: behavior, nervous systems process, postsynapses, enzyme binding; downregulated (DR) were cellular component organization, RNA metabolic process, and signal transduction. Lastly, the intersection of DEGs in the three databases showed eight shared genes between brain and blood, with potential use as AD biomarkers for blood tests.

Autophagy: A Key Regulator of Homeostasis and Disease: An Overview of Molecular Mechanisms and Modulators.

Autophagy is a highly conserved lysosomal degradation pathway active at basal levels in all cells. However, under stress conditions, such as a lack of nutrients or trophic factors, it works as a survival mechanism that allows the generation of metabolic precursors for the proper functioning of the cells until the nutrients are available. Neurons, as post-mitotic cells, depend largely on autophagy to maintain cell homeostasis to get rid of damaged and/or old organelles and misfolded or aggregated proteins. Therefore, the dysfunction of this process contributes to the pathologies of many human diseases. Furthermore, autophagy is highly active during differentiation and development. In this review, we describe the current knowledge of the different pathways, molecular mechanisms, factors that induce it, and the regulation of mammalian autophagy. We also discuss its relevant role in development and disease. Finally, here we summarize several investigations demonstrating that autophagic abnormalities have been considered the underlying reasons for many human diseases, including liver disease, cardiovascular, cerebrovascular diseases, neurodegenerative diseases, neoplastic diseases, cancers, and, more recently, infectious diseases, such as SARS-CoV-2 caused COVID-19 disease.

Bioactive Foods Decrease Liver and Brain Alterations Induced by a High-Fat-Sucrose Diet through Restoration of Gut Microbiota and Antioxidant Enzymes.

Obesity is associated with cognitive deficit and liver alterations; however, it remains unclear whether a combination of functional foods could reverse cognitive damage and to what extent it would be associated with changes in gut microbiota and liver. With this aim, male Wistar rats were fed a high-fat-5%sucrose diet (HFS) for 4 mo. And were then fed for 1 mo. with bioactive foods. At the end of this period, liver, serum, feces, intestine, and brain samples were taken. Body composition, energy expenditure, LPS, hormones, intraperitoneal glucose tolerance test, behavioral tests, and gut microbiota were evaluated. We showed that male rats fed high-fat-sucrose diet developed gut microbiota dysbiosis, increased in body fat, decreased antioxidant activity, decreased brain neuropeptide Y, increased the number of astrocytes and activated microglia, along with reduced spine density associated with deficits in working memory. Ingestion of a combination of nopal, soy protein, curcumin, and chia seed oil (bioactive foods) for three months was associated with an increase in a cluster of bacteria with anti-inflammatory capacity, a decrease in serum LPS levels and an increase in serum eicosapentaenoic acid (EPA) with neuroprotective properties. In the liver, ingestion of bioactive food significantly increased antioxidant enzymes, decreased lipogenesis, reduced inflammation mediated by the TLR4-TNFα pathway along with a decrease in body fat, glucose intolerance, and metabolic inflexibility. Finally, neuroinflammation in the brain was reduced and working memory improved. Our study demonstrates that consumption of bioactive foods was associated with reduced liver, brain, and gut microbiota alterations in obese rats.

Las zonas neurogénicas en el adulto y su relación con las enfermedades neuropsiquiátricas / Neurogenic regions in the adult: Relationship with the neuropsychiatric disorders

Neuropsychiatric diseases (NPD) are characterized by changes in brain plasticity involving alterations in the morphology and functionality of neurons. However, affectations of the neuronal development (neurogenesis) in the adult brain are also shown. The neurogenic process is widely regulated by different factors such as genes, microenvironment, hormones, neurotransmitters, environmental cues and, also, nutrition. Thus, alterations in these factors negatively impact the neuronal development. Several studies performed in humans have revealed alterations of neurogenesis in NPD. However, most of the knowledge derives from studies done in animal models of NPD. The evidences from animal models are controversial, thus the use of human-induced pluripotent stem cells as a model of NPD has marked a way to study alterations in the neuronal development. Recently, the use of another cellular model for studying NPD has been proposed. Multipotent stem cells derived from olfactory epithelium (MOESCs) are a good candidate. However, evidences are scarce and deeper studies are necessary to know if there is or not a correlation of alterations in neuronal development in the OE with the changes observed in the brain; or if the MOESCs can mimic alterations shown in NPD that could let to get more knowledge about the factors promoting these diseases. Thus, in this review we discuss basic information about adult neurogenesis under physiological and non-physiological conditions in the hippocampus, olfactory bulb and olfactory epithelium.

Las enfermedades neuropsiquiátricas (ENP) se caracterizan por cambios en la plasticidad cerebral que incluyen la pérdida neuronal en regiones específicas en el encéfalo, cambios en la transmisión sináptica originada por alteraciones en los contactos sinápticos y también por la expresión de genes. Además, otro proceso que forma parte de la plasticidad cerebral y que también se encuentra afectado en las ENP es la generación de nuevas neuronas (neurogénesis). El proceso neurogénico en el adulto es regulado de manera fina por diversos factores como los aspectos genéticos, celulares, el microambiente, los elementos neuroquímicos, los ambientales y los nutricionales. Las alteraciones de estos factores impactan en el desarrollo y en la función de las nuevas neuronas. Algunos estudios realizados en humanos han revelado las alteraciones en la neurogénesis en algunos ENP. Sin embargo los mayores avances logrados han utilizado modelos animales de ENP. En algunos casos estas evidencias son controvertidas y recientemente se han tratado de aclarar utilizando cultivos de células madre pluripotenciales-inducibles humanas como modelos de ENP. Otro modelo que se ha propuesto para estudiar las alteraciones en el desarrollo neuronal en las ENP son las células madre multipotenciales del epitelio olfatorio (CMPEO). Sin embargo las evidencias obtenidas con las CMPEO son escasas y resulta necesario demostrar si existe o no un correlato con las alteraciones que ocurren en el desarrollo neuronal a nivel central en las ENP, o bien si las CMPEO pueden mostrar las alteraciones observadas en las ENP que permitan obtener información acerca de los factores que promueven estas enfermedades. Por lo tanto en esta revisión se incluyen aspectos básicos de la neurogénesis e información relevante de las alteraciones de este proceso en las tres regiones neurogénicas en el adulto: el hipocampo, el bulbo olfatorio y el epitelio olfatorio.