Disrupted hippocampal performance underlies psychiatric comorbidities and cognitive impairments in patients with neurodegenerative disorders. To understand the contribution of adult hippocampal ...neurogenesis (AHN) to amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, dementia with Lewy bodies, and frontotemporal dementia, we studied postmortem human samples. We found that adult-born dentate granule cells showed abnormal morphological development and changes in the expression of differentiation markers. The ratio of quiescent to proliferating hippocampal neural stem cells shifted, and the homeostasis of the neurogenic niche was altered. Aging and neurodegenerative diseases reduced the phagocytic capacity of microglia, triggered astrogliosis, and altered the microvasculature of the dentate gyrus. Thus, enhanced vulnerability of AHN to neurodegeneration might underlie hippocampal dysfunction during physiological and pathological aging in humans.
The hippocampus hosts the continuous addition of new neurons throughout life—a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian ...species, including humans, and discuss the further validation of these data by single‐cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long‐standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high‐quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research field.
The hippocampus is one of the most affected areas in Alzheimer's disease (AD)
. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of ...new neurons throughout life
. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry
. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.
Evidences for Adult Hippocampal Neurogenesis in Humans Moreno-Jiménez, Elena P; Terreros-Roncal, Julia; Flor-García, Miguel ...
The Journal of neuroscience,
2021-Mar-24, 2021-03-24, 20210324, Letnik:
41, Številka:
12
Journal Article
Recenzirano
Odprti dostop
The rodent hippocampus generates new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is a striking form of neural plasticity that occurs in the brains of numerous ...mammalian species. Direct evidence of adult neurogenesis in humans has remained elusive, although the occurrence of this phenomenon in the human dentate gyrus has been demonstrated in seminal studies and recent research that have applied distinct approaches to birthdate newly generated neurons and to validate markers of adult-born neurons. Our data point to the persistence of AHN until the 10th decade of human life, as well as to marked impairments in this process in patients with Alzheimer's disease. Moreover, our work demonstrates that the methods used to process and analyze postmortem human brain samples can limit the detection of various markers of AHN to the point of making them undetectable. In this Dual Perspectives article, we highlight the critical methodological aspects that should be strictly controlled in human studies and the robust evidence that supports the occurrence of AHN in humans. We also put forward reasons that may account for current discrepancies on this topic. Finally, the unresolved questions and future challenges awaiting the field are highlighted.
Fusion oncogenes (FOs) are common in many cancer types and are powerful drivers of tumor development. Because their expression is exclusive to cancer cells and their elimination induces cell ...apoptosis in FO-driven cancers, FOs are attractive therapeutic targets. However, specifically targeting the resulting chimeric products is challenging. Based on CRISPR/Cas9 technology, here we devise a simple, efficient and non-patient-specific gene-editing strategy through targeting of two introns of the genes involved in the rearrangement, allowing for robust disruption of the FO specifically in cancer cells. As a proof-of-concept of its potential, we demonstrate the efficacy of intron-based targeting of transcription factors or tyrosine kinase FOs in reducing tumor burden/mortality in in vivo models. The FO targeting approach presented here might open new horizons for the selective elimination of cancer cells.
Abstract Several studies have shown the potential of biocompatible lipid nanocapsules as hydrophobic drug delivery systems. Understanding the factors that determine the interactions of these ...oil-in-water nanoemulsions with cells is a necessary step to guide the design of the most effective formulations. The aim of this study was to probe the ability of two surfactants with a markedly different nature, a non-ionic poloxamer, and a charged phospholipid, to prepare formulations with shells of different composition and different surface properties. Thus we determined their effects on the interaction with biological environments. In particular, we investigated how the shell formulation affected the adsorption of biomolecules from the surrounding biological fluids on the nanocapsule surface (corona formation). A complete physicochemical characterization including an isothermal titration calorimetry (ITC) study revealed that the use of poloxamer led to nanocapsules with a marked reduction in the number of protein-binding sites. Surface hydrophilicity and changes in corona formation strongly correlated to changes in uptake by cancer cells and by macrophages. Our results indicate that the nature and concentration of surfactants in the nanocapsules can be easily manipulated to effectively modulate their surface architecture with the aim of controlling the environmental interactions, thus optimizing functionality for in vivo applications. In particular, addition of surfactants that reduce protein binding can modulate nanoparticle clearance by the immune system, but also screens the desired interactions with cells, leading to lower uptake, thus lower therapeutic efficacy. The two effects need to be balanced in order to obtain successful formulations.
Adult hippocampal neurogenesis enhances brain plasticity and contributes to the cognitive reserve during aging. Adult hippocampal neurogenesis is impaired in neurological disorders, yet the molecular ...mechanisms regulating the maturation and synaptic integration of new neurons have not been fully elucidated. GABA is a master regulator of adult and developmental neurogenesis. Here we engineered a novel retrovirus encoding the fusion protein Gephyrin:GFP to longitudinally study the formation and maturation of inhibitory synapses during adult hippocampal neurogenesis in vivo. Our data reveal the early assembly of inhibitory postsynaptic densities at 1 week of cell age. Glycogen synthase kinase 3 Beta (GSK-3β) emerges as a key regulator of inhibitory synapse formation and maturation during adult hippocampal neurogenesis. GSK-3β-overexpressing newborn neurons show an increased number and altered size of Gephyrin
+
postsynaptic clusters, enhanced miniature inhibitory postsynaptic currents, shorter and distanced axon initial segments, reduced synaptic output at the CA3 and CA2 hippocampal regions, and impaired pattern separation. Moreover, GSK-3β overexpression triggers a depletion of Parvalbumin
+
interneuron perineuronal nets. These alterations might be relevant in the context of neurological diseases in which the activity of GSK-3β is dysregulated.
The application of a novel UV fs Laser Ablation Ionization Mass Spectrometry approach for chemical depth profiling of low-melting point, high surface roughness SnAg solder bump features is presented. ...The obtained submicrometer resolved three-dimensional compositional data reveal unprecedented information on the distribution of individual elements inside the solder bump matrix. Moreover, the determination of matrix-matched relative sensitivity coefficients allows the first report on quantitative assessment of the SnAg alloy composition. These results significantly contribute to an in-depth understanding of the SnAg plating process. This experimental procedure may find application in future additive performance screening.
Purpose
A controlled, prospective, multicenter, randomized trial to compare primary patency after angioplasty with a drug-coated balloon versus plain angioplasty balloon in stenosis of dysfunctional ...fistulae and grafts for hemodialysis.
Materials and Methods
A total of 136 patients (148 angioplasties) at four centers were randomized to receive a drug-coated balloon or plain angioplasty balloon after satisfactory angioplasty with a high-pressure balloon. The inclusion criteria were clinical signs of vascular dysfunction confirmed by Doppler Ultrasound and/or angiography. The primary endpoint was target lesion patency defined as time elapsed between the completion of effective and the appearance of restenosis at 6 and 12 months after angioplasty. Secondary endpoints included the relationship between the location of the stenosis, previous angioplasty, demographic variables and survival.
Results
Primary patency after angioplasty was higher in the group treated with the drug-coated balloon than the plain angioplasty balloon (153.01 to 141.69 days at 6 months; 265.78 to 237.83 days at 12 months). Drug-coated balloon angioplasty resulted in superior patency after 6 and 12 months, but this result was not statically significant (
P
= 0.068 at 6 months;
P
= 0.369 at 12 months). There was no relation between target lesion patency and the other variables studied. Overall mortality in the plain angioplasty balloon group was higher (9% vs. 5.7%) but not statistically significant.
Conclusions
Drug-coated balloon angioplasty resulted in superior survival of dysfunctional peripheral vascular access at 6 and 12 months, but this result was not statistically significant. Both arms show equivalent complications and similar mortality.
Level of Evidence
Level Ia, therapeutic study, RCT. EBM ratings will be based on a scale of 1-5.
In this study, we assessed the association between single‐nucleotide polymorphisms (SNPs) in seven candidate genes involved in orchestrating the immune response against cytomegalovirus (CMV) and the ...12‐month incidence of CMV infection in 315 CMV‐seropositive kidney transplant (KT) recipients. Patients were managed either by antiviral prophylaxis or preemptive therapy. CMV infection occurred in 140 patients (44.4%), including 13 episodes of disease. After adjusting for various clinical covariates, patients harboring T‐allele genotypes of interleukin‐28B (IL28B) (rs12979860) SNP had lower incidence of CMV infection (adjusted hazard ratio aHR: 0.66; 95% confidence interval CI: 0.46–0.96; p‐value = 0.029). In the analysis restricted to patients not receiving prophylaxis, carriers of the TT genotype of toll‐like receptor 9 (TLR9) (rs5743836) SNP had lower incidence of infection (aHR: 0.61; 95% CI: 0.38–0.96; p‐value = 0.035), whereas the GG genotype of dendritic cell‐specific ICAM 3‐grabbing nonintegrin (DC‐SIGN) (rs735240) SNP exerted the opposite effect (aHR: 1.86; 95% CI: 1.18–2.94; p‐value = 0.008). An independent association was found between the number of unfavorable SNP genotypes carried by the patient and the incidence of CMV infection. In conclusion, specific SNPs in IL28B, TLR9 and DC‐SIGN genes may play a role in modulating the susceptibility to CMV infection in CMV‐seropositive KT recipients.
Using a large multicenter cohort of seropositive kidney transplant recipients, this study demonstrates the independent effect on the incidence of cytomegalovirus infection of single‐nucleotide polymorphisms in various genes involved in orchestrating innate and adaptive immune responses.
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