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Brain Research Jul 2024A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein...
A Disintegrin And Metalloprotease 10 (ADAM10), is able to control several important physiopathological processes through the shedding of a large number of protein substrates. Although ADAM10 plays a crucial role in the central nervous system (CNS) development and function, its protein distribution in the CNS has not been fully addressed. Here, we described the regional and cellular ADAM10 protein expression in C57BL/6 mice examined by immunofluorescence 1) throughout the adult mouse brain, cerebellum and spinal cord in vivo and 2) in different cell types as neurons, astrocytes, oligodendrocytes and microglia in vitro. We observed ADAM10 expression through the whole CNS, with a strong expression in the hippocampus, in the hypothalamus and in the cerebral and piriform cortex in the brain, in the Purkinje and in granular cell layers in the cerebellum and in the spinal cord to a lower extent. In vivo, ADAM10 protein expression was mainly found in neurons and in some oligodendroglial cell populations. However, in primary cultures we observed ADAM10 expression in neurons, oligodendrocytes, astrocytes and microglia. Interestingly, ADAM10 was not only found in the membrane but also in cytoplasmic vesicles and in the nucleus of primary cultured cells. Overall, this work highlights a wide distribution of ADAM10 throughout the CNS. The nuclear localization of ADAM10, probably due to its intracellular domain, emphasizes its role in cell signalling in physiological and pathological conditions. Further investigations are required to better elucidate the role of ADAM10 in glial cells.
Topics: Animals; ADAM10 Protein; Mice, Inbred C57BL; Neurons; Mice; Membrane Proteins; Central Nervous System; Spinal Cord; Amyloid Precursor Protein Secretases; Astrocytes; Microglia; Cells, Cultured; Oligodendroglia; Male; Brain; Cerebellum
PubMed: 38548249
DOI: 10.1016/j.brainres.2024.148888 -
Annals of Clinical and Translational... Feb 2024Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have...
OBJECTIVE
Postmortem examination of the essential tremor cerebellum has revealed a variety of pathological changes centered in and around Purkinje cells. Studies have predominantly focused on cerebellar neuronal connections. Bergmann glial morphology has not yet been studied in essential tremor. Among their many roles, Bergmann glia in the cerebellar cortex ensheath Purkinje cell synapses and provide neuroprotection. Specifically, the complex radial processes and lateral appendages of Bergmann glia are structural domains that modulate Purkinje cell synaptic transmission. In this study, we investigate whether Bergmann glia morphology is altered in the essential tremor cerebellum.
METHODS
We applied the Golgi-Kopsch method and used computerized three-dimensional cell reconstruction to visualize Bergmann glia in the postmortem cerebellum of 34 cases and 17 controls. We quantified morphology of terminal structures (number of terminations and lateral appendage density) and morphology of radial processes (total process length, branch length, branch order, and branch volume) in each glial cell. We quantified number of branches and volume as well.
RESULTS
Essential tremor cases had a 31.9% decrease in process terminations and a 35.7% decrease in lateral appendage density in Bergmann glia. Total process length and branch length did not differ between essential tremor cases and controls. We found also a reduction in number of secondary and tertiary branches and tertiary branches volume.
INTERPRETATION
These findings suggest that Bergmann glia in essential tremor cases have more alterations in their terminal structures, with a relative preservation of radial processes, and highlight a potential role for these astrocytes in the disease pathophysiology.
Topics: Humans; Essential Tremor; Neuroglia; Purkinje Cells; Astrocytes; Cerebellum
PubMed: 38098226
DOI: 10.1002/acn3.51958 -
Journal of Integrative Neuroscience Aug 2023The cerebellum is an area of the brain that is prone to damage in individuals with Alzheimer's disease (AD). As a non-pharmacological intervention for AD, exercise...
BACKGROUND
The cerebellum is an area of the brain that is prone to damage in individuals with Alzheimer's disease (AD). As a non-pharmacological intervention for AD, exercise training has shown an ameliorating effect on AD pathology; however, the target regions have mostly been the cerebral cortex and hippocampus. The main aim of this study was to explore the influence of 12 weeks of treadmill running on the accumulation of AD-related proteins, dysfunction of mitochondria, and subsequent neuronal cell death in the cerebellum of triple transgenic (3xTg-AD) mice.
METHODS
Four-month-old 3xTg-AD mice were allocated into two groups: an AD control group (AD, n = 10) and an AD exercise group (AD-Exe, n = 10). The AD-Exe mice underwent training on a motorized animal treadmill 5 days a week for 12 weeks. After sacrifice, the cerebellum was collected and biochemically analyzed.
RESULTS
The AD-Exe mice expressed reduced levels of extracellular β-amyloid plaques and phosphorylated tau (p-tau), and showed improved Purkinje cell survival and mitochondrial function compared with AD mice.
CONCLUSIONS
These findings suggest that engaging in exercise training can offer protection against the progression of AD in the cerebellum by enhancing mitochondrial function and promoting cell survival.
Topics: Humans; Animals; Mice; Infant; Alzheimer Disease; Cell Survival; Cerebellum; Animals, Genetically Modified; Mitochondria
PubMed: 37735133
DOI: 10.31083/j.jin2205117 -
Animals : An Open Access Journal From... Sep 2023Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies...
Tauopathies are a group of neurodegenerative diseases characterized by the pathological aggregation of hyperphosphorylated tau in neurons and glia. Primary tauopathies are not uncommon in humans but exceptional in other species. We evaluate the clinical, neuropathological, and genetic alterations related to tau pathology in 16 cats aged from 1 to 21 years with different clinical backgrounds. Interestingly, a 10-year-old female cat presented a six-year progressive history of mental status and gait abnormalities. The imaging study revealed generalized cortical atrophy. Due to the poor prognosis, the cat was euthanatized at the age of ten. Neuropathological lesions were characterized by massive neuronal loss with marked spongiosis and associated moderate reactive gliosis in the parietal cortex, being less severe in other areas of the cerebral cortex, and the loss of Purkinje cells of the cerebellum. Immunohistochemical methods revealed a 4R-tauopathy with granular pre-tangles in neurons and coiled bodies in oligodendrocytes. Deposits were recognized with several phospho-site antibodies (4Rtau, tau5, AT8, PFH, tau-P Thr181, tau-P-Ser 262, tau-P Ser 422) and associated with increased granular expression of active tau kinases (p38-P Thr180/Tyr182 and SAPK/JNK-P Thr138/Thr185). The genetic study revealed well-preserved coding regions of No similar alterations related to tau pathology were found in the other 15 cats processed in parallel. To our knowledge, this is the first case reporting a primary 4R-tauopathy with severe cerebral and Purkinje cell degeneration in an adult cat with neurological signs starting at a young age.
PubMed: 37760385
DOI: 10.3390/ani13182985 -
Journal of Neuropathology and... Apr 2024Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus...
Two aspects of the neuropathology of early Huntington disease (HD) are examined. Neurons of the neostriatum are counted to determine relative loss in striosomes versus matrix at early stages, including for the first time in preclinical cases. An immunohistochemical procedure is described that tentatively distinguishes early HD from HD mimic disorders in postmortem brains. Counts of striatal projection neurons (SPNs) in striosomes defined by calbindin immunohistochemistry versus counts in the surrounding matrix are reported for 8 Vonsattel grade 0 (including 5 premanifest), 8 grade 1, 2 grade 2 HD, and for 8 control postmortem brains. Mean counts of striosome and matrix SPNs were significantly lower in premanifest grade 0 versus controls, with striosome counts significantly lower than matrix. In 8 grade 1 and 2 grade 2 brains, no striosomes with higher SPN counts than in the surrounding matrix were observed. Comparing dorsal versus ventral neostriatum, SPNs in dorsal striosomes and matrix declined more than ventral, making clear the importance of the dorsoventral site of tissue selection for research studies. A characteristic pattern of expanded polyglutamine-immunopositive inclusions was seen in all HD cases. Inclusions were always present in some SPNs and some pontine nucleus neurons and were absent in Purkinje cells, which showed no obvious cell loss.
Topics: Humans; Huntington Disease; Corpus Striatum; Neostriatum; Neurons; Calbindins
PubMed: 38553027
DOI: 10.1093/jnen/nlae022 -
JCI Insight Apr 2024Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic...
Dysregulated lipid homeostasis is emerging as a potential cause of neurodegenerative disorders. However, evidence of errors in lipid homeostasis as a pathogenic mechanism of neurodegeneration remains limited. Here, we show that cerebellar neurodegeneration caused by Sorting Nexin 14 (SNX14) deficiency is associated with lipid homeostasis defects. Recent studies indicate that SNX14 is an interorganelle lipid transfer protein that regulates lipid transport, lipid droplet (LD) biogenesis, and fatty acid desaturation, suggesting that human SNX14 deficiency belongs to an expanding class of cerebellar neurodegenerative disorders caused by altered cellular lipid homeostasis. To test this hypothesis, we generated a mouse model that recapitulates human SNX14 deficiency at a genetic and phenotypic level. We demonstrate that cerebellar Purkinje cells (PCs) are selectively vulnerable to SNX14 deficiency while forebrain regions preserve their neuronal content. Ultrastructure and lipidomic studies reveal widespread lipid storage and metabolism defects in SNX14-deficient mice. However, predegenerating SNX14-deficient cerebella show a unique accumulation of acylcarnitines and depletion of triglycerides. Furthermore, defects in LD content and telolysosome enlargement in predegenerating PCs suggest lipotoxicity as a pathogenic mechanism of SNX14 deficiency. Our work shows a selective cerebellar vulnerability to altered lipid homeostasis and provides a mouse model for future therapeutic studies.
Topics: Sorting Nexins; Animals; Mice; Homeostasis; Lipid Metabolism; Humans; Purkinje Cells; Disease Models, Animal; Neurodegenerative Diseases; Mice, Knockout; Cerebellum; Male; Lipid Droplets
PubMed: 38625743
DOI: 10.1172/jci.insight.168594 -
Scientific Reports Sep 2023Patients with cerebellar stroke display relatively mild ataxic gaits. These motor deficits often improve dramatically; however, the neural mechanisms of this improvement...
Patients with cerebellar stroke display relatively mild ataxic gaits. These motor deficits often improve dramatically; however, the neural mechanisms of this improvement have yet to be elucidated. Previous studies in mouse models of gait ataxia, such as ho15J mice and cbln1-null mice, have shown that they have a dysfunction of parallel fiber-Purkinje cell synapses in the cerebellum. However, the effects of cerebellar stroke on the locomotor kinematics of wild-type mice are currently unknown. Here, we performed a kinematic analysis of gait ataxia caused by a photothrombotic stroke in the medial, vermal, and intermediate regions of the cerebellum of wild-type mice. We used the data and observations from this analysis to develop a model that will allow locomotive prognosis and indicate potential treatment regimens following a cerebellar stroke. Our analysis showed that mice performed poorly in a ladder rung test after a stroke. During walking on a treadmill, the mice with induced cerebellar stroke had an increased duty ratio of the hindlimb caused by shortened duration of the swing phase. Overall, our findings suggest that photothrombotic cerebellar infarction and kinematic gait analyses will provide a useful model for quantification of different types of acute management of cerebellar stroke in rodents.
Topics: Humans; Animals; Mice; Gait Ataxia; Stroke; Gait; Walking; Mice, Knockout
PubMed: 37737224
DOI: 10.1038/s41598-023-42817-4 -
Experimental Neurology Sep 2023Dystonia is a neurological movement disorder characterized by repetitive, unintentional movements and disabling postures that result from sustained or intermittent...
Dystonia is a neurological movement disorder characterized by repetitive, unintentional movements and disabling postures that result from sustained or intermittent muscle contractions. The basal ganglia and cerebellum have received substantial focus in studying DYT1 dystonia. It remains unclear how cell-specific ∆GAG mutation of torsinA within specific cells of the basal ganglia or cerebellum affects motor performance, somatosensory network connectivity, and microstructure. In order to achieve this goal, we generated two genetically modified mouse models: in model 1 we performed Dyt1 ∆GAG conditional knock-in (KI) in neurons that express dopamine-2 receptors (D2-KI), and in model 2 we performed Dyt1 ∆GAG conditional KI in Purkinje cells of the cerebellum (Pcp2-KI). In both of these models, we used functional magnetic resonance imaging (fMRI) to assess sensory-evoked brain activation and resting-state functional connectivity, and diffusion MRI to assess brain microstructure. We found that D2-KI mutant mice had motor deficits, abnormal sensory-evoked brain activation in the somatosensory cortex, as well as increased functional connectivity of the anterior medulla with cortex. In contrast, we found that Pcp2-KI mice had improved motor performance, reduced sensory-evoked brain activation in the striatum and midbrain, as well as reduced functional connectivity of the striatum with the anterior medulla. These findings suggest that (1) D2 cell-specific Dyt1 ∆GAG mediated torsinA dysfunction in the basal ganglia results in detrimental effects on the sensorimotor network and motor output, and (2) Purkinje cell-specific Dyt1 ∆GAG mediated torsinA dysfunction in the cerebellum results in compensatory changes in the sensorimotor network that protect against dystonia-like motor deficits.
Topics: Mice; Animals; Dystonia; Dystonia Musculorum Deformans; Cerebellum; Corpus Striatum; Molecular Chaperones
PubMed: 37321386
DOI: 10.1016/j.expneurol.2023.114471 -
Nutrients Oct 2023Obesity and heavy metals, such as lead (Pb), are detrimental to the adult brain because they impair cognitive function and structural plasticity. However, the effects of...
Obesity and heavy metals, such as lead (Pb), are detrimental to the adult brain because they impair cognitive function and structural plasticity. However, the effects of co-administration of Pb and a high-fat diet (HFD) on the developing cerebellum is not clearly elucidated. We investigated the effects of Pb exposure (0.3% lead acetate) on developing cerebellum in the pups of an HFD-fed obese rat model. One week before mating, we fed a chow diet (CD) or HFD to the rats for one week and additionally administered Pb to HFD-fed female SD rats. Thereafter, treatment with Pb and a HFD was continued during the gestational and lactational periods. On postnatal day 21, the pups were euthanized to sample the brain tissue and blood for further analysis. Blood Pb levels were significantly higher in HFD-fed rats than in CD-fed rats. Histologically, the prominent degeneration of Purkinje cells was induced by the co-administration of Pb and HFD. The calbindin-28Kd-, GAD67-, NMDAR1-, and PSD95-immunopositive Purkinje cells and inhibitory synapse-forming pinceau structures were significantly decreased following Pb and HFD co-administration. MBP-immunoreactive myelinated axonal fibers were also impaired by HFD but were significantly damaged by the co-administration of HFD and Pb. Oxidative stress-related Nrf2-HO1 signaling was activated by HFD feeding, and Pb exposure further aggravated oxidative stress, as demonstrated by the consumption of endogenous anti-oxidant in HFD-Pb rats. The pro-inflammatory response was also increased by the co-administration of HFD and Pb in the cerebellum of the rat offspring. The present results suggest that HFD and Pb treatment during the gestational and lactational periods are harmful to cerebellar development.
Topics: Rats; Animals; Female; Humans; Diet, High-Fat; Lead; Rats, Sprague-Dawley; Cerebellum; Obesity; Prenatal Exposure Delayed Effects
PubMed: 37892401
DOI: 10.3390/nu15204325 -
Acta Histochemica Et Cytochemica Oct 2023Autism is a neurodevelopmental disorder that impairs communication and social interaction. This study investigated the possible beneficial effects of erythropoietin...
Autism is a neurodevelopmental disorder that impairs communication and social interaction. This study investigated the possible beneficial effects of erythropoietin (EPO) on experimental autistic-like behaviors induced by propionic acid (PPA). Twenty-four rats were distributed into three groups: (i) control; (ii) PPA_Gp: daily injected subcutaneously with PPA for five consecutive days; PPA+EPO-Gp: injected with PPA, then received intraperitoneal injection of EPO once daily for two weeks. Behavioral changes in the rats were assessed. Specimens from the cerebellar hemispheres were subjected to histological and ultrastructure examination, immunohistochemistry for glial fibrillary acidic protein (GFAP) and calbindin-D28K, and biochemical analysis for glutathione peroxidase (GSH-Px), malondialdehyde (MDA), gamma amino-butyric acid (GABA), and serotonin. PPA-Gp showed significant behavioral impairment, with a significant depletion in GSH-px, GABA, and serotonin and a significant increase in MDA. Histological examination revealed reduced Purkinje cell count with ultrastructural degeneration, irregularly arranged nerve fibers in the molecular layer, astrogliosis, and significantly decreased calbindin-immunostaining compared to the control. EPO protected cerebellar structure, increased Purkinje cell count, improved neuronal morphology, reduced PPA-induced autistic-like features, alleviated neuronal oxidative stress, increased intercellular antioxidant levels, and suppressed inflammation. EPO provided significant protection against PPA-induced autistic features in rats, with structural preservation of Purkinje cells.
PubMed: 37970239
DOI: 10.1267/ahc.23-00027