Two of the most predominant features of the Alzheimer’s disease (AD) brain are deposition of β-amyloid (Aβ) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there ...is evidence to suggest that inflammation may predate the deposition of Aβ. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain’s immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.
Systemic inflammation has been implicated in the progression of many neurodegenerative diseases and may be an important driver of the disease. Dementia and cognitive decline progress more rapidly ...following acute systemic infection, and systemic inflammation midlife is predictive of the degree of cognitive decline. Plasmin, the active form of the serine protease plasminogen (PLG), is a blood protein that plays physiological roles in fibrinolysis, wound healing, cell signaling, extracellular matrix degradation, and inflammatory regulation.
Mice were treated with an antisense oligonucleotide to deplete liver-produced PLG prior to systemic challenge with lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria, known to induce a strong immune response in animals. Following treatment, the innate immune response in the brains of these animals was examined.
Mice that were PLG-deficient had dramatically reduced microgliosis and astrogliosis in their brains after LPS injection. We found that blood PLG regulates the brain's innate immune response to systemic inflammatory signaling, affecting the migration of perivascular macrophages into the brain after challenge with LPS.
Depletion of plasma PLG with an antisense oligonucleotide dramatically reduced glial cell activation and perivascular macrophage migration into the brain following LPS injection. This study suggests a critical role for PLG in mediating communication between systemic inflammatory mediators and the brain.
Inflaming the Brain Ahn, Hyung Jin; Baker, Sarah K.; Norris, Erin H. ...
Neuron,
03/2019, Letnik:
101, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini et al. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and ...cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.
Exactly how cerebrovascular alterations contribute to Alzheimer's disease (AD) is still unknown. Merlini et al. (2019) show that blood-derived fibrinogen leads to dendritic spine elimination and cognitive deficit via microglial CD11b/CD18. Fibrinogen may be a significant contributor to AD pathogenesis.
Physical activity mass media campaigns can deliver physical activity messages to many people, but it remains unclear whether they offer good value for money. We aimed to investigate the ...cost-effectiveness, cost-utility, and costs of physical activity mass media campaigns. A search for economic evaluations (trial- or model-based) and costing studies of physical activity mass media campaigns was performed in six electronic databases (June/2021). The authors reviewed studies independently. A GRADE style rating was used to assess the overall certainty of each modelled economic evaluation. Results were summarised via narrative synthesis. Twenty-five studies (five model-based economic evaluations and 20 costing studies) were included, and all were conducted in high-income countries except for one costing study that was conducted in a middle-income country. The methods and assumptions used in the model-based analyses were highly heterogeneous and the results varied, ranging from the intervention being more effective and less costly (dominant) in two models to an incremental cost of US$130,740 (2020 base year) per QALY gained. The level of certainty of the models ranged from very low (n = 2) to low (n = 3). Overall, intervention costs were poorly reported. There are few economic evaluations of physical activity mass media campaigns available. The level of certainty of the models was judged to be very low to low, indicating that we have very little to little confidence that the results are reliable for decision making. Therefore, it remains unclear to what extent physical activity mass media campaigns offer good value for money. Future economic evaluations should consider selecting appropriate and comprehensive measures of campaign effectiveness, clearly report the assumptions of the models and fully explore the impact of assumptions in the results.
The membrane properties and conduction velocities of antidromically activated medial septum-diagonal band (MS-DB) neurons
were examined using whole-cell recordings in a longitudinally cut rat brain ...slice preparation containing the MS-DB and the
dorsal fornix.
MS-DB neurons were divided into three groups according to their action potential characteristics and firing properties. Slow
firing neurons displayed a broad action potential followed by a prominent after-hyperpolarization. Burst firing neurons, when
depolarized from hyperpolarized holding potentials, exhibited a high-frequency burst of spikes on the crest of a slow depolarizing
potential. Fast firing neurons did not fire bursts of spikes when depolarized from hyperpolarized holding potentials.
Eighteen MS-DB neurons were identified as septohippocampal by antidromic activation. Of the septohippocampal neurons, four
were slow firing neurons, five were burst firing neurons and nine were fast firing neurons. The mean axon conduction velocities
of these neurons fell into two significant groups, termed slow conducting and fast conducting. Slow firing septohippocampal
neurons had significantly slower conduction velocities than either fast firing or burst firing neurons ( P < 0.05), being 0.7 ± 0.5 ms â1 for slow firing neurons and 2.9 ± 2.0 and 2.0 ± 1.4 ms â1 for burst firing and fast firing neurons, respectively.
On the basis of previous evidence which has linked firing properties with the neurochemical identities of the neurons, we
propose that the slow firing septohippocampal neurons are cholinergic whereas the burst firing and fast firing septohippocampal
neurons are GABAergic.
Hearing loss is a common sensory deficit and more than 50% of affected individuals have a genetic etiology. The discovery of 40 genes and more than 100 loci involved in hearing loss has made genetic ...testing for some of these genes widely available. Genetic services for deafness are also being sought more often due to the early identification of hearing loss through newborn screening services. The motivations for pursuing genetic testing, and how genetic services are provided to the client may differ among individuals. Additionally, information obtained through genetic testing can be perceived and used in different ways by parents of deaf children and deaf adults. This study aimed to follow up on focus group studies published earlier with a quantitative survey instrument and assess the preference of consumers for provision of genetic services. We conducted a national survey of hearing and deaf parents of children with hearing loss and of deaf adults. Data was compared and analyzed by hearing status of the participant, their community affiliation and the genetic testing status using nominal logistic regression. Consistent with our focus group results, the survey participants thought that a genetic counselor/geneticist would be the most appropriate professional to provide genetics services. Statistically significant differences were noted in the preferred choice of provider based on the genetic testing status. Parents preferred that genetic evaluation, including testing, occur either immediately at or a few months after the audiologic diagnosis of hearing loss. This data should help providers in clinical genetics keep patient preferences at the helm and provide culturally competent services.
The fate of parthenogenetic cells was investigated during development of fetal and early postnatal chimeras. On day 13 of embryonic development, considerable contribution of parthenogenetic cells was ...observed in all tissues of chimeric embryos, although selection against parthenogenetic cells seemed to start before day 13. Between days 13 and 15 of development, parthenogenetic cells came under severe selective pressure, which was most striking in tongue. The disappearance of parthenogenetic cells from tongue coincided with the beginning of myoblast fusion in this tissue. Severe selection against parthenogenetic cells was also observed in pancreas and liver, although in the latter, parthenogenetic cells were eliminated later than in skeletal muscle or pancreas. In other tissues, parthenogenetic cells may persist and participate to a considerable extent throughout the gestation period and beyond, although a significant decrease was observed in all tissues. Parthenogenetic in equilibrium fertilized chimeras were significantly smaller than their non-chimeric littermates at all developmental stages. These results suggest that the absence of paternal chromosomes is largely incompatible with the maintenance of specific differentiated cell types. Furthermore, paternally derived genes seem to be involved in the regulation of proliferation of all cell types, as indicated by the drastic growth decceleration of parthenogenetic in equilibrium fertilized chimeras and the overall decrease of parthenogenetic cells during fetal development. Chromosomal imprinting may have a role in maintaining a balance between cell growth and differentiation during embryonic development. The major exception to the selective elimination of parthenogenetic cells appear to be the germ cells; viable offspring derived from parthenogenetic oocytes were detected, sometimes at a high frequency in litters of female parthenogenetic in equilibrium fertilized chimeras.
We have examined the role of germline-specific chromosomal determinants of development in the mouse. Studies were carried out using aggregation chimaeras between androgenetic---fertilized embryos and ...compared with similar parthenogenetic---fertilized chimaeras. Several adult chimaeras were found with parthenogenetic cells but none were found with androgenetic cells. Analysis of chimaeras at mid-gestation showed that parthenogenetic cells were detected in the embryo and yolk sac but that androgenetic cells were found only in the trophoblast and yolk sac and not in the embryo. The contribution of parthenogenetic cells to the embryo and yolk sac was increased by aggregating 2-cell parthenogenetic and 4-cell fertilized embryos but the contribution of parthenogenetic cells in extraembryonic tissues remained negligible even after aggregation of 4-cell parthenogenetic and 2-cell fertilized embryos. Furthermore, parthenogenetic cells were primarily found in the yolk sac mesoderm and not in the yolk sac endoderm. These results suggest that maternal chromosomes in parthenogenetic cells permit their participation in the primitive ectoderm lineage but these cells are presumably eliminated by selective pressure or autonomous cell lethality from the primitive endoderm and trophectoderm lineages. Conversely paternal chromosomes in androgenetic cells confer opposite properties since the embryonic cells can be detected in the trophoblast and the yolk sac but not in the embryos, presumably because they are eliminated from the primitive ectoderm lineage. The spatial distribution of cells with different parental chromosomes may occur partly because of differential expression of some genes, such as proto-oncogenes, and partly due to their ability to respond to a variety of diffusible growth factors.
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