Search

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant four

Parkinson's disease (PD) is a highly prevalent and irreversible neurodegenerative disorder that is typically diagnosed in an advanced stage. Currently, there are no approved biomarkers that reliably identify PD patients before they have undergone extensive neuronal damage, eliminating the opportunity for future disease-modifying therapies to intervene in disease progression. This unmet need for diagnostic and therapeutic biomarkers has fueled PD research for decades, but these efforts have not yet yielded actionable results. Recently, studies exploring mechanisms underlying PD progression have offered insights into multisystemic contributions to pathology, challenging the classic perspective of PD as a disease isolated to the brain. This shift in understanding has opened the door to potential new biomarkers from multiple sites in the body. This review focuses on emerging candidates for PD biomarkers in the context of current diagnostic approaches and multiple organ systems that contribute to disease.

BATTAGLIA, GIORGIO, 4415, open, RATIONALE: We previously demonstrated in a rat model of chronic epilepsy associated with cortical malformations, the methylazoxymethanol (MAM)-pilocarpine -MP- rats, that status epilepticus (SE) and subsequent seizures set in motion a maladaptive plasticity altering the morphology of cortical pyramidal neurons and NMDA receptor expression and localization. We have here exploited the same model to verify i) the activation of cell death pathways in both neurons and glia during the course of epilepsy and ii) whether these changes could be related to epilepsy course. METHODS: MAM rats treated with pilocarpine and diazepam (MDP, n=5), not experiencing SE, were used as controls. MP rats were analyzed at 18h after SE (acute phase, MP-acute, n=3), 3-5 days after epilepsy onset (early chronic phase, MP-EC, n=3) and 3 and 6 months after epilepsy onset (chronic phase, MP-3m, n=8, MP-6m, n=5). Morphometric analysis of neocortex and hippocampus was performed and cell degeneration assessed with Fluoro-Jade (FJ) staining. We also used single- and double-labeling immunocytochemistry to study the activation of different pathways possibly leading to cell death. RESULTS: Our morphometric analysis revealed progressively reduced cortical thickness and hippocampal and thalamic volumes during chronic epilepsy course. FJ analysis revealed the activation of cell death processes not temporally restricted to the primary insult of pilo-induced SE, but extending to the different epileptic stages considered up to 6 months (Fig 1). We also found a region-specific pattern of FJ activation, degenerating neurons being more evident at early chronic epileptic stages in cortex and thalamus and at late chronic stages in hippocampal CA layers. Granule cells were consistently FJ- throughout all stages. Reactive astrocytes with larger cell bodies, thicker processes, and more eccentric nuclei became increasingly evident. Caspase3 and c-Jun activation became also progressive in chronic MP rats. Double IF exp, No, open, Nobili, Nobili, P

RATIONALE: We previously demonstrated in a rat model of chronic epilepsy associated with cortical malformations, the methylazoxymethanol (MAM)-pilocarpine -MP- rats, that status epilepticus (SE) and subsequent seizures set in motion a maladaptive plasticity altering the morphology of cortical pyramidal neurons and NMDA receptor expression and localization. We have here exploited the same model to verify i) the activation of cell death pathways in both neurons and glia during the course of epilepsy and ii) whether these changes could be related to epilepsy course. METHODS: MAM rats treated with pilocarpine and diazepam (MDP, n=5), not experiencing SE, were used as controls. MP rats were analyzed at 18h after SE (acute phase, MP-acute, n=3), 3-5 days after epilepsy onset (early chronic phase, MP-EC, n=3) and 3 and 6 months after epilepsy onset (chronic phase, MP-3m, n=8, MP-6m, n=5). Morphometric analysis of neocortex and hippocampus was performed and cell degeneration assessed with Fluoro-Jade (FJ) staining. We also used single- and double-labeling immunocytochemistry to study the activation of different pathways possibly leading to cell death. RESULTS: Our morphometric analysis revealed progressively reduced cortical thickness and hippocampal and thalamic volumes during chronic epilepsy course. FJ analysis revealed the activation of cell death processes not temporally restricted to the primary insult of pilo-induced SE, but extending to the different epileptic stages considered up to 6 months (Fig 1). We also found a region-specific pattern of FJ activation, degenerating neurons being more evident at early chronic epileptic stages in cortex and thalamus and at late chronic stages in hippocampal CA layers. Granule cells were consistently FJ- throughout all stages. Reactive astrocytes with larger cell bodies, thicker processes, and more eccentric nuclei became increasingly evident. Caspase3 and c-Jun activation became also progressive in chronic MP rats. Double IF exp

AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.

AIM: This study aimed to develop a 3D culture model to test the extent to which transplanted stem cells modulate astrocyte reactivity, where exacerbated glial cell activation could be detrimental to CNS repair success. MATERIALS & METHODS: The reactivity of rat astrocytes to bone marrow mesenchymal stem cells, neural crest stem cells (NCSCs) and differentiated adipose-derived stem cells was assessed after 5 days. Schwann cells were used as a positive control. RESULTS: NCSCs and differentiated Schwann cell-like adipose-derived stem cells did not increase astrocyte reactivity. Highly reactive responses to bone marrow mesenchymal stem cells and Schwann cells were equivalent. CONCLUSION: This approach can screen therapeutic cells prior to in vivo testing, allowing cells likely to trigger a substantial astrocyte response to be identified at an early stage. NCSCs and differentiated Schwann cell-like adipose-derived stem cells may be useful in treating CNS damage without increasing astrogliosis.