In this review, we focus on the emerging roles of microglia in the brain, with particular attention to synaptic plasticity in health and disease. We present evidence that ramified microglia, ...classically believed to be "resting" (i.e., inactive), are instead strongly implicated in dynamic and plastic processes. Indeed, there is an intimate relationship between microglia and neurons at synapses which modulates activity-dependent functional and structural plasticity through the release of cytokines and growth factors. These roles are indispensable to brain development and cognitive function. Therefore, approaches aimed at maintaining the ramified state of microglia might be critical to ensure normal synaptic plasticity and cognition. On the other hand, inflammatory signals associated with Alzheimer's disease are able to modify the ramified morphology of microglia, thus leading to synapse loss and dysfunction, as well as cognitive impairment. In this context, we highlight microglial TREM2 and CSF1R as emerging targets for disease-modifying therapy in Alzheimer's disease (AD) and other neurodegenerative disorders.
Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aβ ...accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aβ-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aβ. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aβ from glutamatergic terminals. We believe that the selective pruning of Aβ-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.
The TICON (TIdal CONstants) dataset contains harmonic constants of 40 tidal constituents computed for 1,145 tide gauges distributed globally. The tidal estimations are based on publicly available sea ...level records of the second version of the Global Extreme Sea Level Analysis (GESLA) project and were derived through a least squares‐based harmonic analysis on the single time series. A preliminary screening was performed on all records to exclude doubtful observations. Only the records containing more than 70% of valid measurements were processed, that correspond to 89.7% of the total 1,276 original public GESLA records. The results are stored in a text file, and include additional information on the position of the stations, the starting and ending years of the analysed record, the estimated error of the fit, a code that corresponds to the source of the record and additional information on the single time series. In ocean tide models, data from in situ stations are used for validation purposes, and TICON is a useful and easy‐to‐handle data set that allows the users to select the records according to different criteria most suitable for their purposes. The data are provided with DOI identification in the PANGAEA repository.
Since the launch of the first altimetry satellites, ocean tide models have been improved dramatically for deep and shallow waters. However, issues are still found for areas of great interest for ...climate change investigations: the coastal regions. The purpose of this study is to analyze the influence of the ALES coastal retracker on tide modeling in these regions with respect to a standard open ocean retracker. The approach used to compute the tidal constituents is an updated and along-track version of the Empirical Ocean Tide model developed at DGFI-TUM. The major constituents are derived from a least-square harmonic analysis of sea level residuals based on the FES2014 tide model. The results obtained with ALES are compared with the ones estimated with the standard product. A lower fitting error is found for the ALES solution, especially for distances closer than 20 km from the coast. In comparison with in situ data, the root mean squared error computed with ALES can reach an improvement larger than 2 cm at single locations, with an average impact of over 10% for tidal constituents K 2 , O 1 , and P 1 . For Q 1 , the improvement is over 25%. It was observed that improvements to the root-sum squares are larger for distances closer than 10 km to the coast, independently on the sea state. Finally, the performance of the solutions changes according to the satellite’s flight direction: for tracks approaching land from open ocean root mean square differences larger than 1 cm are found in comparison to tracks going from land to ocean.
Background
Microglia cells are primary players in neuroinflammation, which plays a key role in the pathogenesis of Alzheimer's disease (AD). Under pathological inflammatory conditions, microglia ...activation leads to synaptic alterations thereby influencing the progression of AD. Increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). Using electrophysiological and immunohistochemical analysis, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether pharmacological manipulation of microglia activation could restore the observed neuroplasticity alterations.
Method
C57BL6/J mices of both sexes aged between 30‐ and 40‐days were used. Employing electrophysiological approaches (field and whole cell patch clamp), we recorded in area CA1 in response to stimulation of Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation measuring field Excitatory Post‐Synaptic Potentials (fEPSPs) 1 hour after tetanization. We also investigated paired‐pulse ratio (PPR) and spontaneous EPSCs (sEPSCs). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of scrambled Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10μM) and Minocycline (500 nM). For immunohistochemical experiments free‐floating sections were incubated with primary antibodies overnight at 4°C followed by Alexa‐conjugated secondary antibody and DAPI for 2 hours at room temperature in the dark. VGLUT1, Iba1 and CD68 were used as synaptic marker in a triple staining to study pathological pruning and its reversal by PLX‐3397.
Result
Both inflammatory models induced LTP impairment, that was restored by application of a no‐specific blocker, Minocycline, or a specific inhibitor of activated microglia, PLX‐3397.Using whole cell patch clamp recordings, we observed that Aβ produces a reduction in glutamatergic transmission, evaluated as amplitude or frequency of sEPSCs and PPR, that is prevented by PLX‐3397. The data were confirmed using imaging studies, by which count of CA1 microglia and spine remodeling were evaluated.
Conclusion
Our results demonstrate a functional role of activated microglia in synaptic plasticity alteration that occurs in neuroinflammation suggesting CSF1R as new pharmacological target for AD treatment.
Background
Neuroinflammation has demonstrated a key role in the pathogenesis of Alzheimer disease (AD). Among the innate immune cells, microglia are the primary players in neuroinflammation. When ...microglia is activated under pathological inflammatory conditions, it can lead to synaptic alterations thereby influencing the progression of AD. Among other mechanisms, an increased activation of microglial colony stimulating factor 1 receptor (CSF1R) can lead to pathological microglia activation in experimental models of AD (Olmos‐Alonso et al., 2016). In this work, using electrophysiological techniques, we investigated hippocampal synaptic transmission and plasticity in experimental models of neuroinflammation. We then tested whether the pharmacological manipulation of microglia activation was able to restore the neuroplasticity alterations associated with these models.
Method
The experiments were conducted using C57BL6/J mice of both sexes aged between 30‐ and 40‐days. Using electrophysiological approach (field and whole cell patch clamp), we performed recordings in area CA1 in response to stimulation of the Schaffer collaterals. We evaluated Long‐Term Potentiation (LTP) induced by theta‐burst stimulation. Responses were recorded for 1 hour after tetanization and measured as field Excitatory Post‐Synaptic Potential (fEPSP). Two in vitro inflammatory models were obtained applying Lipopolysaccharide (LPS) (10 μg/ml) or Aβ 1‐42 oligomers (200 nM). As a control, we tested the effect of Aβ 1‐42 with a scrambled sequence applied in the same condition of Aβ 1‐42. To inhibit the activation of microglia we used Pexidartinib (PLX‐3397) (10 μM), a specific inhibitor of activated microglia, and Minocycline (500 nM) a no‐specific blocker.
Result
Slices treated with Aβ 1‐42 and LPS showed impairment of LTP. Indeed, LTP was fully suppressed after exposition to oligomeric Aβ while no change of fEPSP was observed after incubation of slices with Aβ scrambled. Similarly, a selective inhibition of LTP was observed in the presence of LPS. Minocycline application reversed synaptic dysfunction in slices treated with Aβ 1‐42 and LPS. Preliminary data also indicate that PLX‐3397 rescues LTP impairment mediated by oligomeric Aβ.
Conclusion
Our data show a functional role of activated microglia in the synaptic plasticity alteration induced by neuroinflammation and suggest CSF1R as an emerging target in the treatment of AD.
Numerous clinical trials of anti‐amyloid agents for Alzheimer’s disease (AD) were so far unsuccessful thereby challenging the validity of the amyloid hypothesis. This lack of progress has encouraged ...researchers to investigate alternative mechanisms in non-neuronal cells, among which microglia represent nowadays an attractive target. Microglia play a key role in the developing brain and contribute to synaptic remodeling in the mature brain. On the other hand, the intimate relationship between microglia and synapses led to the so-called synaptic stripping hypothesis, a process in which microglia selectively remove synapses from injured neurons. Synaptic stripping, along with the induction of a microglia-mediated chronic neuroinflammatory environment, promote the progressive synaptic degeneration in AD. Therefore, targeting microglia may pave the way for a new disease modifying approach. This review provides an overview of the pathophysiological roles of the microglia cells in AD and describes putative targets for pharmacological intervention. It also provides evidence for microglia-targeted strategies in preclinical AD studies and in early clinical trials.
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EOT20 is the latest in a series of empirical ocean tide (EOT) models derived using residual tidal analysis of multi-mission satellite altimetry at
DGFI-TUM. The amplitudes and phases of 17 tidal ...constituents are provided on a global 0.125∘ grid based on empirical analysis of
seven satellite altimetry missions and four extended missions. The EOT20 model shows significant improvements compared to the previous iteration of
the global model (EOT11a) throughout the ocean, particularly in the coastal and shelf regions, due to the inclusion of more recent satellite
altimetry data as well as more missions, the use of the updated FES2014 tidal model as a reference to estimated residual signals, the inclusion of
the ALES retracker and improved coastal representation. In the validation of EOT20 using tide gauges and ocean bottom pressure data, these
improvements in the model compared to EOT11a are highlighted with the root sum square (RSS) of the eight major tidal constituents improving by
∼ 1.4 cm for the entire global ocean with the major improvement in RSS (∼ 2.2 cm) occurring in the coastal
region. Concerning the other global ocean tidal models, EOT20 shows an improvement of ∼ 0.2 cm in RSS compared to the closest model
(FES2014) in the global ocean. Variance reduction analysis was conducted comparing the results of EOT20 with FES2014 and EOT11a using the Jason-2,
Jason-3 and SARAL satellite altimetry missions. From this analysis, EOT20 showed a variance reduction for all three satellite altimetry missions
with the biggest improvement in variance occurring in the coastal region. These significant improvements, particularly in the coastal region,
provide encouragement for the use of the EOT20 model as a tidal correction for satellite altimetry in sea-level research. All ocean and load tide
data from the model can be freely accessed at https://doi.org/10.17882/79489 (Hart-Davis et al., 2021). The tide gauges from the TICON dataset used in the validation of the tide model, are available at https://doi.org/10.1594/PANGAEA.896587 (Piccioni et al., 2018a).
In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical ...phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.
In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor’s clinical ...phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer’s disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.
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