Astrogliosis

…measuring amyloid and tau deposition, astrogliosis and synapse impairment together with cognitive tests, CSF, plasma biomarke

Astrocytic dysfunctions have increasingly been recognized as a significant element in epilepsy pathophysiology. The prominent expression of connexin channels is one of the key features of astrocytes, essential for their extensive intercellular coupling. It is currently debated whether astrocytic connexins have pro- or anti-epileptic effects. The existence of two types of connexins, namely Cx30 and Cx43, which display different properties as well as several functions beyond gap junction formation, such as hemichannel constituents or signaling elements, further makes it more complex to investig

Cerebral adrenoleukodystrophy (CALD) is an X-linked inflammatory demyelinating disorder leading to death within a few years. CALD can be halted by hematopoietic stem cell transplantation (HSCT) or gene therapy (GT) when applied at early disease stages. Currently, eligibility for treatment is determined by MRI-based brain lesion Loes scoring. However, this grading system poorly reflects later disease stages or atypical lesion patterns. As such, there is a need for alternative biomarkers to help with treatment decisions. We recently identified inflammatory activity and CALD progression being ref

Neuroinflammation is a fundamental element of many neurodegenerative disorders. Activation of astrocytes and microglia cells leads to a release of cytokines and reactive oxygen species followed by leakage of the blood-brain barrier and neurotoxicity. Transient neuroinflammation is understood to be largely protective, chronic neuroinflammation, however, contributes to the pathology of Alzheimer’s disease, traumatic brain injury, and many more. In this study, we focus on the aspect of cytokine-induced neuroinflammation in human microglia cells and especially in astrocytes, since many studies on

The main pathological hallmark of Parkinson’s disease (PD) and related synucleinopathies is the presence of intracellular proteinaceous aggregates, enriched in the presynaptic protein alpha-Synuclein (α-Syn). α-Syn association with exosomes has been previously documented both as a physiological process of secretion and as a pathological process of disease transmission, however, critical information about the mechanisms governing this interplay is still lacking. To address this, we utilized the α-Syn preformed fibril (PFF) mouse model of PD, as a source of brain-derived exosome-enriched extrace

Blood biomarkers are becoming increasingly important for clinical trial stratification and healthcare. Therefore this work explored these existing markers’ diagnostic accuracy and ability to differentially diagnose Dementia with Lewy Bodies (DLB) from Alzheimer’s Disease (AD). A multi-modal, combinatorial approach was taken to validate plasma and PET imaging markers’ utilities.The singular and combined ability of two emerging phospho-tau markers, p-tau217 and p-tau231, to differentiate DLB from AD was tested in a well-characterised cohort of patients over the age of 50. Following from this, pl

Mucopolysaccharidosis type II (MPS II) is a rare X-linked recessive lysosomal storage disease (LSD) caused by mutations of iduronate-2- sulfatase (IDS), a lysosomal enzyme involved in heparan and dermatan sulfate degradation. In pathological conditions, the abnormal storage of these molecules leads to a range of multisystemic symptoms affecting the central nervous system (CNS), which is extremely vulnerable to impaired lysosomal function. Indeed, LSDs neuropathological manifestations often involve microglial and astrocyte activation.In this context, I took advantage of an ids-mutant zebrafish

Atypical astrocytes (AtAs) are a distinct subset of non-reactive astrocytes in the brain characterized by dramatically diminished expression of excitatory amino acid transporters (GLAST, GLT1) and other astrocytic proteins. Our ongoing research on the development and progression of AtAs in naïve wild type (WT) mice has shown significant regional and age effects. We have also shown that brain tissue from confirmed Alzheimer’s Disease (AD) patients, as well as healthy controls, have areas of presumptive AtAs. This study aims to further explore the role of AtAs in AD pathology utilizing the APPNL

Hypoxic-ischaemic encephalopathy (HIE) is one of the most serious complications in neonates and infants. Mesenchymal stromal cell (MSC)-based therapy is emerging as a promising treatment avenue for HIE. However, despite its enormous potential, the clinical application of MSCs is limited by cell heterogeneity, low isolation efficiency and unpredictable effectiveness. In this study, we investigated the therapeutic effects of human pluripotent stem cell-derived ectomesenchymal stromal cells (hPSC-EMSCs) and human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) in a rat model of HIE. Lesi

…plasticity deficits, neuronal loss and astrogliosis. Astrocytes, recognized partners of neurons in brain function, are characterized by a signaling system based on variations in intracellular Ca2+ concentration. Experi

The restrictive element-1 silencing transcription factor (REST) is a transcriptional repressor which acts via epigenetic remodeling to silence numerous target genes. Emerging evidence indicates that REST is a master regulator of neuron-specific genes, not only in neurogenesis and neuronal differentiation, but also in differentiated neurons during postnatal brain development, where it plays a role in fine-tuning of genes involved in synaptic plasticity, and in normal aging, where it promotes neuroprotection by repressing genes involved in oxidative stress and dementia. However, un aberrant REST

Neurodegenerative diseases like Alzheimer’s disease and Progressive Supranuclear Palsy (PSP) exhibit synaptic loss. In these conditions, synaptic loss precedes neuronal degeneration, and the degree of synaptic loss correlates closely with the severity of clinical symptoms. Both Aβ, which accumulates in amyloid plaques in AD, and tau protein which accumulates intracellularly in tauopathies, accumulate within synaptic terminals. In model systems, the accumulation of Aβ and tau in synapses has been linked to synaptic dysfunction, synaptic loss, and the spread of pathology trans-synaptically. Howe

…atrophy, neuronal loss, and astrogliosis. However, detailed neuropathological studies characterising the human XDP striatum are limited.To advance our understanding of the human XDP striatum, immunohistochemistry coupled with automated analysis was conducted on post-mortem striatal tissue from 12 XDP and 5 age-matched neurologically normal cases to detail (1) the neurochemical architecture and (2) neuronal and glial populations

The transcription factor Nrf2 (encoded by the Nfe2l2 gene) is a widely-expressed stress-responsive master regulator of several aspects of homeostatic physiology. Nrf2 plays a key role in preventing oxidative stress and inflammation. In the brain, Nrf2 is highly expressed by endothelial cells. Brain endothelial cells (BECs) are the key component of the blood brain barrier (BBB), which controls brain homeostasis. The role of BEC Nrf2 expression in maintaining homeostasis is not fully understood. In this project, through gain- and loss function experiments, we have found that Nrf2 activity in BEC

The neurodegenerative process in Parkinson’s disease involves exacerbated inflammation with the participation of astrocytes. The P2Y1 receptor (P2Y1R) is a purinergic receptor predominantly expressed in astrocytes, regulating their activity, proliferation, and glutamate release. Therefore, our investigation explores whether the P2Y1R contributes to dopaminergic neuron degeneration, potentially via astrocytic involvement. To study dopaminergic degeneration, we injected 9 µg 6-hydroxydopamine into the right striatum (STR) of male Sprague-Dawley rats aged 6-8 weeks (ethical approval: 167/2019). D

Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a common target for treating PD's motor symptoms. However, we have little understanding of STN pathology in PD. We aimed to examine the cellular and functional pathology of the STN in PD using both rodent and post-mortem human brain tissue. First, we show bidirectional motor control by STN using optogenetic modulation, where inhibition of the STN increases movement and STN activation decreases movement. We also examined the effect of bidirectional optogenetic m

Traumatic brain injury (TBI) is a cause of disability and a risk factor for the development of epilepsy, partially mediated by reactive gliosis. The aim of this project was to observe astroglial and microglial reactions to brain injury and identify sex differences in the process of glial scar formation.Penetrating cortical brain injury was induced on postnatal day 30 (P30) in male and female rats. The animals were perfused on P32, P38, P46, or P60. Brain tissue was sectioned and stained against glial fibrillary acidic protein (GFAP, astrocyte marker) and ionized calcium-binding adapter molecul

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the formation of amyloid-β (Aβ) plaques and Tau neurofibrillary tangles, leading to neuronal loss, inflammation, reduced neurogenesis, and cognitive impairment. Currently, there is no effective cure for AD, highlighting the urgent need for novel therapeutic strategies. Growth hormone-releasing hormone (GHRH) and its agonistic analog MR-409 exhibit several peripheral functions, including neuroprotection and protection against skeletal muscle atrophy. However, the role of GHRH in AD remains to be elucidated. Our in vitro f

Pathologically activated connexin hemichannels can establish a self-propagating inflammasome activation loop that may contribute to Alzheimer’s disease (AD). This study aims to investigate the potential of modulating the inflammasome loop through connexin hemichannel blockade in a mouse model of AD known to display neurodegeneration, neuroinflammation, and memory deficits. One day after intrahippocampal injection of aggregated amyloid beta 1-42 (AB1-42), treatment mice (n=8) were administered a connexin hemichannel blocker, Tonabersat, in a peanut butter pellet for 16 days before tissue collec

The proportion of aged individuals in the general population is increasing, and non-communicable diseases like obesity are major contributors to mortality in older individuals. The WNIN/Ob obese rat exhibits a significantly reduced average lifespan of 15 months. Exploring molecular and biochemical characteristics of these rats can establish them as appropriate model for studying the neurobiology of aging and obesity.We investigated the growth characteristics and lifespan of WNIN/Obobese rats, examined neuronal-glial changes, levels of oxidative stress, antioxidant enzyme activity, and DNA dama

Astrocytes are multifunctional glial cells, implicated in neurogenesis and synaptogenesis, supporting and fine-tuning neuronal activity and maintaining brain homeostasis by controlling blood-brain barrier permeability. During the last years a number of studies have shown that astrocytes can also be converted into neurons if they force-express neurogenic transcription factors or miRNAs. Direct astrocytic reprogramming to induced-neurons (iNs) is a powerful approach for manipulating cell fate, as it takes advantage of the intrinsic neural stem cell (NSC) potential of brain resident reactive astr

Dravet syndrome is a severe epileptic encephalopathy that begins during the first year of life and leads to severe cognitive and social interaction deficits. It is mostly caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes for the alpha-subunit of the voltage-gated sodium channel (Nav1.1) and is responsible mainly of GABAergic interneuron excitability. While different therapies based on the upregulation of the healthy allele of the gene are being developed, the dynamics of reversibility of the pathology are still unclear. In fact, whether and to which extent the