Dysfunction and recovery of synapses in prion disease: implications for neurodegeneration

2010 ◽  
Vol 38 (2) ◽  
pp. 482-487 ◽  
Author(s):  
Julie A. Moreno ◽  
Giovanna R. Mallucci
Keyword(s):  
Cell Death ◽  
Prion Disease ◽  
Neurodegenerative Disorders ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Adult Brain ◽  
Synaptic Dysfunction ◽  
Synapse Loss ◽  
Physiological Processes ◽  
Temporal Segregation

Synaptic dysfunction is a key early process in many neurodegenerative diseases, but how this ultimately leads to neuronal loss is not clear. In health, there is ongoing remodelling of synapses and spines in the adult brain: their elimination and formation are continual physiological processes fundamental to learning and memory. But in neurodegenerative disease, including prion disease, lost synapses are not replaced, and their loss is followed by neuronal death. These two processes are separately regulated, with mechanistic, spatial and temporal segregation of the respective death routines of synapses and cell bodies. Mice with prion disease can be cured at the stage of early synaptic dysfunction, when they have reversible impairments at neurophysiological, behavioural and morphological levels. Critically, reversing synaptic dysfunction at this stage of disease rescues neurons, preventing its otherwise inevitable progression to synapse loss and cell death. These findings call for a deeper analysis of the mechanisms underlying neurotoxicity at the synapse, and have important implications for the therapy of prion and other neurodegenerative disorders.

scholarly journals Proneurotrophins Induce Apoptotic Neuronal Death After Controlled Cortical Impact Injury in Adult Mice

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142093086
Author(s):  
Laura E. Montroull ◽  
Deborah E. Rothbard ◽  
Hur D. Kanal ◽  
Veera D’Mello ◽  
Vincent Dodson ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Cell Death ◽  
Brain Injury ◽  
Neuronal Death ◽  
Apoptotic Cell ◽  
Neuronal Cell ◽  
Adult Brain ◽  
Neurotrophin Receptor ◽  
Cortical Impact ◽  
Impact Injury

The p75 neurotrophin receptor (p75NTR) can regulate multiple cellular functions including proliferation, survival, and apoptotic cell death. The p75NTR is widely expressed in the developing brain and is downregulated as the nervous system matures, with only a few neuronal subpopulations retaining expression into adulthood. However, p75NTR expression is induced following damage to the adult brain, including after traumatic brain injury, which is a leading cause of mortality and disability worldwide. A major consequence of traumatic brain injury is the progressive neuronal loss that continues secondary to the initial trauma, which ultimately contributes to cognitive decline. Understanding mechanisms governing this progressive neuronal death is key to developing targeted therapeutic strategies to provide neuroprotection and salvage cognitive function. In this study, we demonstrate that a cortical impact injury to the sensorimotor cortex elicits p75NTR expression in apoptotic neurons in the injury penumbra, confirming previous studies. To establish whether preventing p75NTR induction or blocking the ligands would reduce the extent of secondary neuronal cell death, we used a noninvasive intranasal strategy to deliver either siRNA to block the induction of p75NTR, or function-blocking antibodies to the ligands pro-nerve growth factor and pro-brain-derived neurotrophic factor. We demonstrate that either preventing the induction of p75NTR or blocking the proneurotrophin ligands provides neuroprotection and preserves sensorimotor function.

scholarly journals Change in tau phosphorylation associated with neurodegeneration in the ME7 model of prion disease

2010 ◽  
Vol 38 (2) ◽  
pp. 545-551 ◽  
Author(s):  
Ayodeji A. Asuni ◽  
V. Hugh Perry ◽  
Vincent O'Connor
Keyword(s):  
Axonal Transport ◽  
Prion Disease ◽  
Neuronal Loss ◽  
Brain Homogenate ◽  
Tau Phosphorylation ◽  
Synaptic Dysfunction ◽  
Normal Brain ◽  
Hyperphosphorylated Tau ◽  
Ad Alzheimer’S Disease ◽  
End Stage

Hyperphosphorylation of the microtubule-associated protein tau is a significant determinant in AD (Alzheimer's disease), where it is associated with disrupted axonal transport and probably causes synaptic dysfunction. Although less well studied, hyperphosphorylation has been observed in prion disease. We have investigated the expression of hyperphosphorylated tau in the hippocampus of mice infected with the ME7 prion agent. In ME7-infected animals, there is a selective loss of CA1 synapse, first discernable at 13 weeks of disease. There is a potential that dysfunctional axonal transport contributes to this synaptopathy. Thus investigating hyperphosphorylated tau that is dysfunctional in AD could illuminate whether and how they are significant in prion disease. We observed no differences in the levels of phosphorylated tau (using MC1, PHF-1 and CP13 antibodies) in detergent-soluble and detergent-insoluble fractions extracted from ME7- and NBH- (normal brain homogenate) treated animals across disease. In contrast, we observed an increase in phospho-tau staining for several epitopes using immunohistochemistry in ME7-infected hippocampal sections. Although the changes were not of the magnitude seen in AD tissue, clear differences for several phospho-tau species were seen in the CA1 and CA3 of ME7-treated animals (pSer199−202>pSer214>PHF-1 antibody). Temporally, these changes were restricted to animals at 20 weeks and none of the disease-related staining was associated with the axons or dendrites that hold CA1 synapses. These findings suggest that phosphorylation of tau at the epitopes examined does not underpin the early synaptic dysfunction. These data suggest that the changes in tau phosphorylation recorded here and observed by others relate to end-stage prion pathology when early dysfunctions have progressed to overt neuronal loss.

From tau phosphorylation to tau aggregation: what about neuronal death?

2010 ◽  
Vol 38 (4) ◽  
pp. 967-972 ◽  
Author(s):  
Luc Buée ◽  
Laëtitia Troquier ◽  
Sylvie Burnouf ◽  
Karim Belarbi ◽  
Anneke Van der Jeugd ◽  
...  
Keyword(s):  
Cell Death ◽  
Cognitive Impairment ◽  
Neurodegenerative Disorders ◽  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Tau Phosphorylation ◽  
Tau Proteins ◽  
Phosphorylated Tau ◽  
Sequence Of Events

Tau pathology is characterized by intracellular aggregates of abnormally and hyperphosphorylated tau proteins. It is encountered in many neurodegenerative disorders, but also in aging. These neurodegenerative disorders are referred to as tauopathies. Comparative biochemistry of the tau aggregates shows that they differ in both tau isoform phosphorylation and content, which enables a molecular classification of tauopathies. In conditions of dementia, NFD (neurofibrillary degeneration) severity is correlated to cognitive impairment and is often considered as neuronal death. Using tau animal models, analysis of the kinetics of tau phosphorylation, aggregation and neuronal death in parallel to electrophysiological and behavioural parameters indicates a disconnection between cognition deficits and neuronal cell death. Tau phosphorylation and aggregation are early events followed by cognitive impairment. Neuronal death is not observed before the oldest ages. A sequence of events may be the formation of toxic phosphorylated tau species, their aggregation, the formation of neurofibrillary tangles (from pre-tangles to ghost tangles) and finally neuronal cell death. This sequence will last from 15 to 25 years and one can ask whether the aggregation of toxic phosphorylated tau species is a protection against cell death. Apoptosis takes 24 h, but NFD lasts for 24 years to finally kill the neuron or rather to protect it for more than 20 years. Altogether, these data suggest that NFD is a transient state before neuronal death and that therapeutic interventions are possible at that stage.

scholarly journals An Atlas of Phosphorylation and Proteolytic Processing Events During Excitotoxic Neuronal Death Reveals New Therapeutic Opportunities

2020 ◽  
Author(s):  
S. Sadia Ameen ◽  
Antoine Dufour ◽  
M. Iqbal Hossain ◽  
Ashfaqul Hoque ◽  
Sharelle Sturgeon ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Kinases ◽  
Neuronal Death ◽  
Neurological Disorders ◽  
Protein Modification ◽  
Neuronal Loss ◽  
Axonal Guidance ◽  
Death Process ◽  
Molecular Events

SummaryExcitotoxicity, a neuronal death process in neurological disorders, is initiated by over-stimulation of neuronal ionotropic glutamate receptors. The over-stimulated receptors dysregulate proteases, protein kinases and phosphatases, which in turn modify target neuronal proteins to induce cell death. To decipher this cell death mechanism, we used quantitative proteomics, phosphoproteomics and N-terminomics to identify modified proteins in excitotoxic neurons. Data, available in ProteomeXchange (identifiers: PXD019527 and PXD019211), enabled us to identify over one thousand such proteins with calpains, cathepsins and over twenty protein kinases as their major modifiers. These protein modification events can potentially perturb signalling pathways governing cell survival, synaptogenesis, axonal guidance and mRNA processing. Importantly, blocking the modification of Src protein kinase, a signalling hub in excitotoxic neurons, protected against neuronal loss in vivo in a rat model of neurotoxicity. Besides offering new insights into excitotoxic neuronal death mechanism, our findings suggest potential neuroprotective therapeutic targets for treating neurological disorders.Graphical abstractHighlightsMulti-dimensional proteomic analysis identified proteins modified by proteolysis and altered phosphorylation in neurons undergoing excitotoxic cell death.Calpains, cathepsins and over twenty protein kinases are major modifiers of these proteins.These protein modification events are predicted to impact cell survival, axonal guidance, synaptogenesis and mRNA processing.Blocking modification of an identified protein Src, which acts as a major signalling hub in neurons, was protective against excitotoxic injury in vivo.In BriefUsing multidimensional proteomic approaches, Ameen, et al. mapped the changes of proteome, phosphoproteome and N-terminome of cultured primary neurons during excitotoxicity, a crucial neuronal death process in neurological disorders. These proteomic changes document new excitotoxicity-associated molecular events, and offer insights into how these events are organized to induce neuronal death. Potential therapeutic relevance of these molecular events is illustrated by the demonstration that in vivo blockade of one of these events could protect against excitotoxic neuronal loss.

scholarly journals Mechanisms of Neuronal Death in the Cerebral Cortex during Aging and Development of Alzheimer’s Disease-Like Pathology in Rats

2019 ◽  
Vol 20 (22) ◽  
pp. 5632 ◽  
Author(s):  
Darya V. Telegina ◽  
Gleb K. Suvorov ◽  
Oyuna S. Kozhevnikova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Decision Making ◽  
Cell Death ◽  
Cerebral Cortex ◽  
Brain Development ◽  
Brain Region ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Decision Making Behavior

Alzheimer’s disease (AD) is the commonest type of late-life dementia and damages the cerebral cortex, a vulnerable brain region implicated in memory, emotion, cognition, and decision-making behavior. AD is characterized by progressive neuronal loss, but the mechanisms of cell death at different stages of the disease remain unknown. Here, by means of OXYS rats as an appropriate model of the most common (sporadic) AD form, we studied the main pathways of cell death during development of AD-like pathology, including the preclinical stage. We found that apoptosis is activated at the pre-symptomatic stage (age 20 days) correlating with the retardation of brain development in the OXYS strain early in life. Progression of the AD-like pathology was accompanied by activation of apoptosis and necroptosis resulting from a decline of autophagy-mediated proteostasis. Our results are consistent with the idea that the nature of changes in the pathways of apoptosis, autophagy, and necrosis depends on the stage of AD.

scholarly journals Subfield-Specific Neurovascular Remodeling in the Entorhino-Hippocampal-Organotypic Slice Culture as a Response to Oxygen–Glucose Deprivation and Excitotoxic Cell Death

2012 ◽  
Vol 33 (4) ◽  
pp. 508-518 ◽  
Author(s):  
Sophorn Chip ◽  
Cordula Nitsch ◽  
Sven Wellmann ◽  
Josef P Kapfhammer
Keyword(s):  
Cell Death ◽  
Blood Vessels ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Glucose Deprivation ◽  
Vessel Density ◽  
Slice Culture ◽  
Organotypic Slice Culture ◽  
Junction Protein ◽  
Excitotoxic Cell Death

Transient ischemia causes delayed neurodegeneration in selective brain areas, particularly in the CA1 field of the hippocampus. This is accompanied by neurovascular impairment. It is unknown whether neurodegeneration is the cause or consequence of vascular changes. In an entorhino-hippocampal-organotypic slice culture system with well-preserved blood vessels, we studied the interplay between neurodegeneration and neurovasculature. Short-term oxygen and glucose deprivation (OGD) resulted in upregulation of hypoxic markers and with a delay of 24 to 48 hours in selective nerve cell death in CA1. In parallel, local vessel density decreased as detected by markers of endothelial cells and of the extracellular matrix. Claudin-5, a tight junction protein and marker of the blood–brain barrier was reduced. Preventing neuronal death with tetrodotoxin or 6-cyano-7-nitroquinoxaline-2,3-dione rescued blood vessels, suggesting that vessel loss is not due to OGD per se but a consequence of neuronal death. Induction of excitotoxic neuronal death with AMPA caused widespread neurodegeneration, but vessel reduction was confined to CA1. In dentate gyrus without neuronal loss, vessel density increased. We propose that neuronal stress and death influence maintenance, loss and remodeling of the neurovasculature and that the type of vascular response is in addition determined by local factors within the hippocampus.

scholarly journals An autopsy-proven case of Corticobasal degeneration heralded by Pontine infarction

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dallah Yoo ◽  
Sung-Hye Park ◽  
Sungwook Yu ◽  
Tae-Beom Ahn
Keyword(s):  
Neurodegenerative Disorders ◽  
Clinical Manifestations ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Executive Dysfunction ◽  
Lacunar Infarction ◽  
Cortical Atrophy ◽  
Dystonic Posturing ◽  
Proven Case ◽  
The Right

Abstract Background Neurodegenerative disorders are characterized by insidious progression with poorly-delineated long latent period. Antecedent clinical insult could rarely unmask latent neurodegenerative disorders. Here, we report an autopsy-proven case of corticobasal degeneration which was preceded by a lacunar infarction. Case presentation A 58-year-old man presented with acute ataxia associated with a lacunar infarction in the right paramedian pons. His ataxia persisted with additional progressive gait difficulty and left arm clumsiness. Six months later, a follow-up neurological examination showed asymmetrical bradykinesia, apraxia, dystonic posturing, postural instability, and mild ataxia of the left limbs. Cognitive examination revealed frontal executive dysfunction and visuospatial difficulties. Dopamine transporter imaging scan demonstrated bilateral reduced uptakes in mid-to-posterior putamen, more prominent on the right side. Levodopa-unresponsive parkinsonism, asymmetric limb dystonia, and ideomotor apraxia became more conspicuous, while limb ataxia gradually vanished. The patient became unable to walk without assistance after 1 year, and died 4 years after the symptom onset. Autopsy findings showed frontoparietal cortical atrophy, ballooned neurons, and phosphorylated tau-positive astrocytic plaques and neuropil threads with gliosis and neuronal loss, confirming the corticobasal degeneration. Conclusions The case illustrates that precedent clinical events such as stroke might tip a patient with subclinical CBS into overt clinical manifestations.

scholarly journals Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

2020 ◽  
Vol 6 (46) ◽  
pp. eabc1428
Author(s):  
A. Nakano-Kobayashi ◽  
A. Fukumoto ◽  
A. Morizane ◽  
D. T. Nguyen ◽  
T. M. Le ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Inflammatory Responses ◽  
Therapeutic Potential ◽  
Neuronal Survival ◽  
Disease Model ◽  
Neuronal Loss ◽  
Induced Pluripotent Stem Cell ◽  
Related Factor ◽  
Induced Pluripotent ◽  
Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

scholarly journals Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 686
Author(s):  
Maria Concetta Geloso ◽  
Nadia D’Ambrosi
Keyword(s):  
Multiple Sclerosis ◽  
Neuronal Death ◽  
Environmental Changes ◽  
Experimental Models ◽  
Synaptic Dysfunction ◽  
Synapse Elimination ◽  
Neurodegenerative Process ◽  
Immune Mediated ◽  
Wide Range ◽  
Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

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