The clinical-epidemiological relationship between major depressive disorder (MDD) and Alzheimer disease (AD) suggests that they may share common neurobiologic abnormalities.
The authors conducted a ...systematic review and identified microRNAs abnormally expressed in both AD and MDD. The pattern of microRNA regulation in each disorder and the genes regulated by each microRNA and the biologic processes and pathways regulated by these genes were identified.
Seventy-four microRNAs were abnormally expressed in AD and 30 in MDD; 7 were common for both disorders (hsa-let-7f-5p, hsa-miR-664a-3p, hsa-miR-361-5p, hsa-let-7g-5p, hsa-let-7d-5p, hsa-miR-191-5p, hsa-miR-26b-5p). These microRNAs interact with 45 validated genes, and the main biologic pathways and processes regulated by them were proteostasis control, maintenance of genomic integrity, regulation of transcriptional activity, immune-inflammatory control, and neurotrophic support.
The current results suggest that the maintenance of genomic integrity, proteostasis control, immune-inflammatory regulation, and neurotrophic support are key neurobiologic links between these conditions. A comprehensive hypothetical model for the interaction between MDD, aging, and the development of AD is provided.
Alzheimer's disease (AD) is characterized by progressive, irreversible loss of memory and cognitive function. Drosophila melanogaster and other animal models are used to study several diseases, in ...order to elucidate unknown mechanisms and develop potential therapies. Molecular studies require biological samples and, for neuropathologies such as AD biopsy of the human brain, are invasive and potentially damaging. The solution is to use animal models, such as D. melanogaster, which is a model organism that can replace mammalian organisms in such studies. In this study, we evaluated the climbing ability and differential gene expression during AD progression due to the amylodoigenic pathway using RNA-seq, and we performed an in silico analysis of a fruit fly AD-like GFP (Green Fluorescent Protein) model with GFP expression in the pan-neural elav driver. A total of 1388 genes were differentially expressed in all analyzed groups. The main pathways related to those Differentially Expressed Genes (DEGs) during aging and AD progression were evaluated using the fly genes and human orthologs, in order to link genomic information to higher-order functional information with gene pathway mapping. We identified pathways present in all analyzed groups, such as metabolic pathways, ribosomal pathways, proteasome pathways and immune system pathways. Some of the genes were validated by qPCR. Knockdown of CG17754 gene by RNAi promoted degeneration in the fly eye, validating these findings in vivo. The identification of similarities in molecular pathways between the transgenic fly AD-like GFP model and mammals related to AD provides new insights into the use of this fly in screening novel anti-AD drugs.
•Drosophila melanogaster model for Alzheimer disease (AD-like) can be created by using elav-Gal4, UAS-GFP strain.•AD-like model using elav-Gal4, UAS-GFP strain had a delay to beginning the symptoms.•RNA-seq from AD-like GFP model showed a profile gene expressed similar to human.•A novel gene, the CG17754, was validated as candidate for neurodegeneration.
To evaluate the circulating cell-free mitochondrial DNA (ccf-mtDNA) levels, a marker of cellular stress and damage, in older adults with late-life depression (LLD) and frailty. We hypothesize that ...individuals with both frailty and LLD will have higher ccf-mtDNA levels than individuals with either condition in isolation.
Fifty-three older adults (Never Depressed+Robust (reference group, n = 16), LLD+Robust (n = 9), Never Depressed+Prefrail/Frail (n = 5), and LLD+Prefrail/Frail (n = 23)) were included in the study. DNA was extracted from EDTA plasma samples, and ccf-mtDNA was quantified by RT-PCR.
We found a statistically significant difference in the levels of ccf-mtDNA across groups (F
= 3.07, p = 0.036), with individuals in the LLD+Prefrail/Frail group showing the highest levels of ccf-mtDNA.
The coexistence of LLD and frailty is associated with increased markers of cellular damage and stress (i.e., ccf-mtDNA). Our results suggest that these conditions may share cellular stress and mitochondrial dysfunction phenomena as a common biological mechanism, offering potential future opportunities for geroscience-guided interventions for these conditions.
Objectives
Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown ...contradictory results of telomere length (TL) in major depression, and are a few studies in late‐life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults.
Methods/design
We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM‐V criteria), aged 60–90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve.
Results
TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale‐21, r = −0.325, p = .004) and medical burden (r = −0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21).
Conclusions
We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression.
Our study explores and examines the relationship between telomere length (TL) and Late‐Life Depression (LLD), considering the severity of depressive episodes. We found that TL was significantly shorter in the LLD than control participants and was negatively correlated with the severity of depressive symptoms and medical burden. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age‐associated adverse outcomes linked to depression.
Background
Mood disorders such as major depressive (MD) and bipolar (BD), are major risk factors for Alzheimer’s disease (AD). History of MD and BD can double the risk of developing AD in older ...adults, and this risk is even higher when depressive symptoms co‐occur with mild cognitive impairment. These evidences suggest that mood disorders and AD may share common biological mechanisms, such as genetic risk factors. However, challenges on conducting multi‐phenotype long‐follow up studies limit the direct assessment of this hypothesis. Recently, bioinformatics methods using Genome‐wide association studies (GWAS) results have been developed and applied to assess the existence of genetic overlap among disorders. Herein, we carried out a multilevel approach to investigate the genetic overlap between mood disorders (MD and BD) and AD, by assessing their genetic correlation, polygenic overlap and shared biological pathways.
Method
Summary statistics of three large GWAS for MD, BD and AD were assessed. Genetic overlap and correlation were obtained using LDSC and MiXer. ConjFDR was used to identify pleiotropic loci. Finally, a gene‐based approach was applied to obtain a list of overlapping genes and pathways for mood disorders and AD. Pathway enrichment analysis and visualization have been carried out using g:Profiler and Enrichment Map App. Each network (MD&AD, B&AD and MD&BD&AD) was visualized using Cytoscape.
Result
Positive genetic correlation among both mood disorders and AD (rG=0.162; p=0.012 for MD and rG=0.162; p=0.018 for BD&AD) was observed, and further confirmed by all approaches. TMEM106B and THSD7A were identified as pleiotropic candidate genes for MD and MTSS2, VAC14 and FAF1, for BD&AD. Important biological pathways and functions linking these disorders were highlighted, such as acute inflammatory response, programmed cell death, amyloid‐beta response, neuronal death, cell growth, respiratory electron transport chain, lipid metabolism and absorption and membrane trafficking.
Conclusion
Our results confirm for the first time the existence of genetic correlation between mood disorders and AD, identify candidate pleiotropic genes and reinforce the existence of a structured biological network among mood disorders and AD. The results obtained herein, once confirmed, may contribute to shed light on future efforts for precision medicine applied to neurodegenerative and mood disorders and their comorbidities.
The cell cycle is a critical mechanism for proper cellular growth, development and viability. The p16
and p21
are important regulators of the cell cycle progression in response to internal and ...external stimuli (e.g., stress). Accumulating evidence indicates that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces, among others, molecular and morphological alterations, reflecting behavioral changes. Here, we investigated if the p16
and p21
expression are associated with behavioral outcomes.
Prefrontal cortex mRNA and protein levels of p16
and p21
of mice (six independent groups of C57BL/6J, eight mice/group, 50% female) exposed from 0 to 35 days of chronic restraint stress (CRS) were quantified by qPCR and Western Blot, respectively. Correlation analyses were used to investigate the associations between cyclin-dependent kinase inhibitors (CKIs) expression and anxiety- and depression-like behaviors.
Our results showed that the PFC activated the cell cycle regulation pathways mediated by both CKIs p16
and p21
in mice exposed to CRS, with overall decreased mRNA expression and increased protein expression. Moreover, correlation analysis revealed that mRNA and protein levels are statistically significant correlated with anxiety and depressive-like behavior showing a greater effect in males than females.
Our present study extends the existing literature providing evidence that PFC cells respond to chronic stress exposure by overexpressing CKIs. Furthermore, our findings indicated that abnormal expression of p16
and p21
may significantly contribute to non-adaptive behavioral responses.
Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is ...accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes. While rodent models exist for some of the PD-causing mutations, research on the sporadic forms of PD is lagging due to a lack of cellular models. In our study, we differentiated PD patient-derived dopaminergic (DA) neurons from the induced pluripotent stem cells (iPSCs) of several PD-causing mutations as well as from sporadic PD patients. Strikingly, we observed a common neurophysiological phenotype: neurons derived from PD patients had a severe reduction in the rate of synaptic currents compared to those derived from healthy controls. While the relationship between mutations in genes such as the SNCA and LRRK2 and a reduction in synaptic transmission has been investigated before, here we show evidence that the pathogenesis of the synapses in neurons is a general phenotype in PD. Analysis of RNA sequencing results displayed changes in gene expression in different synaptic mechanisms as well as other affected pathways such as extracellular matrix-related pathways. Some of these dysregulated pathways are common to all PD patients (monogenic or idiopathic). Our data, therefore, show changes that are central and convergent to PD and suggest a strong involvement of the tetra-partite synapse in PD pathophysiology.
•No significant differences between the later-life depression (LLD) patients to the control group in terms of the serum EGF and FGF-2 levels.•No any significant correlations between serum levels of ...EGF or FGF2 and MDRS total or individual scores in LLD patients and the control group.•No any significant correlation between the serum EGF and FGF-2 levels and age but EGF is affected by gender in the LLD patients.•Hamilton Depression Rating Scale(HDRS) score is correlated to serum levels of FGF-2 in LLD patients.•Significant correlations between serum levels of EGF and FGF2 in both LLD patients and the control group.
Epidermal growth factor (EGF) and Fibroblast Growth Factor-2 (FGF-2) are growth factors involved neuronal growth and synaptic plasticity. These markers have been implicated in neuropsychiatric disorders, including major depression. However, no particular studies of EGF and FGF-2 have been conducted in older adults with major depressive disorder (MDD). In this study, we aim to investigate the plasma levels of EGF and FGF-2 in elderly with MDD. We included 89 older adults with MDD and 51 older (healthy control, HC) adults. The cognitive performance was evaluated by the Mattis Dementia Rating Scale (MDRS). The EGF and FGF-2 were measured by using multiplex assay for LUMINEX platform. There were also no significant differences between the patient group in terms of plasma levels of EGF and FGF-2 when compared to the HC group. There were not any significant correlations between plasma levels of EGF or FGF2 and MDRS total or individual scores in patient group and HC. There were significant correlations between plasma levels of EGF and FGF2 in both patient group and HC. Further study on plasma levels of EGF and FGF2 should be implemented in larger samples in elderly with MDD.
This work prepared and characterized microcapsule of
Uncaria tomentosa
(UT) in order to standardize a spray-dryer
Uncaria tomentosa
extract. The UT bark powder was subjected to extraction by ...maceration using hydro-ethanol solution. The
Uncaria tomentosa
extract was used to prepare the spray-dryer microcapsules UT-F1. The UT extract and microcapsules UT-F1 were submitted to chemical and physicochemical characterization tests. The phytochemical tests revealed the presence of alkaloids and phenolic compounds such as catechin. The UT extract and microcapsules UT-F1 showed high content of total phenols (28.48% ± 0.76 and 36.34% ± 0.22), high catechin content (47.95% ± 4.90 and 51.15% ± 4.20) and high antioxidant activity with IC
50
values of 5.80 and 5.03 µg cm
−3
. The SEM, FTIR and TG analysis confirmed the morphology of spherical particles, the microencapsulation of the constituents of the UT extract, low moisture content, as well as stability of the microcapsules UT-F1. The DSC analysis and dissolution tests showed the technological influence of spray-dried starch combined UT extract considered water-poorly soluble resulting in vitro release (52.9%) of polyphenolic compounds from
Uncaria tomentosa
microcapsules. The combined use of disintegrants with a natural surfactant in the UT microcapsules has improved the release of polyphenols (catechin) from spray-dryer herbal composition reaching an equivalent release of 78.6% of catechin after 240 min. The in vitro release of microcapsules UT-F1 responds depending on the concentration of pharmaceutical excipients considered disintegrating and can easily achieve release greater than 80%. The microcapsules UT-F1 can be used as bulk material for herbal products in pharmaceutical industry.
Introduction
The biological mechanisms linking mild cognitive impairment (MCI) and major depressive disorder are not well understood. We investigated whether molecular senescence changes in older ...adults are associated with a history of major depressive disorder (MDD) or MCI.
Methods
We included 371 participants: 167 with MCI; 62 cognitively normal with a history of MDD; 97 with MDD+MCI; and 45 cognitively unimpaired (CU) without a history of MDD. The candidate Senescence‐Associated Secretory Phenotype (SASP) biomarkers were measured in the plasma using a customized LUMINEX assay.
Results
The MDD+MCI group had a higher SASP index than the other groups (P < .001). A higher SASP index was significantly associated with worse global cognitive performance, executive dysfunction, slower processing speed, and episodic memory deficits.
Discussion
Our study suggests that increased molecular changes are associated with cognitive impairment in older adults with MDD and indicate that accelerated biological aging is an underlying feature of MDD.
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