Showing papers on "Neurodegeneration published in 2011"
TL;DR: Mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, are examined, and therapeutic opportunities relating to these neurovascular deficits are highlighted.
Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.
2,256 citations
TL;DR: Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination, which will be crucial to the development of therapeutic targets to treat AD.
Abstract: Alzheimer's disease (AD), the leading cause of dementia worldwide, is characterized by the accumulation of the β-amyloid peptide (Aβ) within the brain along with hyperphosphorylated and cleaved forms of the microtubule-associated protein tau. Genetic, biochemical, and behavioral research suggest that physiologic generation of the neurotoxic Aβ peptide from sequential amyloid precursor protein (APP) proteolysis is the crucial step in the development of AD. APP is a single-pass transmembrane protein expressed at high levels in the brain and metabolized in a rapid and highly complex fashion by a series of sequential proteases, including the intramembranous γ-secretase complex, which also process other key regulatory molecules. Why Aβ accumulates in the brains of elderly individuals is unclear but could relate to changes in APP metabolism or Aβ elimination. Lessons learned from biochemical and genetic studies of APP processing will be crucial to the development of therapeutic targets to treat AD.
1,486 citations
TL;DR: A growing body of work about the connections between apoptosis, stem cells, and cancer is explored, focusing on how apoptotic cells release a variety of signals to communicate with their cellular environment, including factors that promote cell division, tissue regeneration, and wound healing.
1,406 citations
TL;DR: Predictive genetic testing and findings of neuroimaging studies show that Huntington's disease is emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.
Abstract: Huntington's disease is a progressive, fatal, neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene, which encodes an abnormally long polyglutamine repeat in the huntingtin protein. Huntington's disease has served as a model for the study of other more common neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. These disorders all share features including: delayed onset; selective neuronal vulnerability, despite widespread expression of disease-related proteins during the whole lifetime; abnormal protein processing and aggregation; and cellular toxic effects involving both cell autonomous and cell-cell interaction mechanisms. Pathogenic pathways of Huntington's disease are beginning to be unravelled, offering targets for treatments. Additionally, predictive genetic testing and findings of neuroimaging studies show that, as in some other neurodegenerative disorders, neurodegeneration in affected individuals begins many years before onset of diagnosable signs and symptoms of Huntington's disease, and it is accompanied by subtle cognitive, motor, and psychiatric changes (so-called prodromal disease). Thus, Huntington's disease is also emerging as a model for strategies to develop therapeutic interventions, not only to slow progression of manifest disease but also to delay, or ideally prevent, its onset.
1,394 citations
TL;DR: It is demonstrated that preformed fibrils generated from full-length and truncated recombinant α-syn enter primary neurons, probably by adsorptive-mediated endocytosis, and promote recruitment of soluble endogenousα-syn into insoluble PD-like LBs and LNs.
1,248 citations
TL;DR: The identification of PARIS provides a molecular mechanism for neurodegeneration due to parkin inactivation, whose levels are regulated by the ubiquitin proteasome system via binding to and ubiquitination by the E3 ubiquitIn ligase, parkin.
825 citations
TL;DR: The mainstay of care for patients with Alzheimer's disease is likely to be the anti-freezing agent, followed by anti-inflammatory drugs and finally a wait-and-see approach to treat the central nervous system disorder.
Abstract: Heat shock proteins (Hsps) comprise a heterogeneous group of highly conserved molecules that are a critical component of proteostasis. Some Hsps are constitutively expressed in cells to promote proper folding and assembly of polypeptides. However, most Hsps are also rapidly induced in response to cellular stress, including oxidative stress and ischemic injury that results in the accumulation of denatured proteins (figure 1). Hsps provide a first line of defense against accumulation of misfolded, aggregation-prone proteins; their neuroprotective effects also include inhibition of apoptosis, cytoskeletal protection, and immune modulation. Hsps are present in the inclusions that characterize several neurodegenerative disorders, such as Alzheimer disease (AD), Parkinson disease (PD), and Huntington disease. Mutations of Hsps have been linked to some forms of distal hereditary motor neuronopathy, axonal Charcot-Marie-Tooth type 2 (CMT2) disease, myofibrillary myopathy, and progressive spastic paraparesis. Hsps are among the most potent suppressors of neurodegeneration in animal models. Thus, Hsps provide a potential target for protective pharmacotherapy in many neurologic disorders. The multiple functions and dynamics of Hsps and their involvement in neurologic diseases have been extensively reviewed.1,–,15
Figure 1 Heat shock response and chaperone functions of heat shock proteins (Hsps)
Accumulation of misfolded proteins during cellular stress is the basic trigger for expression of Hsps, via a feedback loop involving heat shock factor (HSF)-1. HSF-1 is kept in an inactive, monomeric state in the cytoplasm by association with Hsp90. In response to accumulation of misfolded proteins, HSF-1 dissociates from Hsps 90, undergoes trimerization and translocation to the nucleus, and binds to heat shock elements (HSE) in Hsp genes, activating the production of Hsp70, Hsp40, and small Hsps such as Hsp27. The chaperone activity of Hsp90 and Hsp70 requires dynamic conformational changes and adenosine triphosphate (ATP) hydrolysis. Hsp40 interacts with Hsp70, coupling substrate binding with ATP hydrolysis. Once transcribed, small Hsps such as Hsp27 form large oligomeric structures; …
660 citations
TL;DR: The data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.
Abstract: Multiple sclerosis is a chronic inflammatory disease of the central nervous system, associated with demyelination and neurodegeneration. The mechanisms of tissue injury are currently poorly understood, but recent data suggest that mitochondrial injury may play an important role in this process. Since mitochondrial injury can be triggered by reactive oxygen and nitric oxide species, we analysed by immunocytochemistry the presence and cellular location of oxidized lipids and oxidized DNA in lesions and in normal-appearing white matter of 30 patients with multiple sclerosis and 24 control patients without neurological disease or brain lesions. As reported before in biochemical studies, oxidized lipids and DNA were highly enriched in active multiple sclerosis plaques, predominantly in areas that are defined as initial or ‘prephagocytic’ lesions. Oxidized DNA was mainly seen in oligodendrocyte nuclei, which in part showed signs of apoptosis. In addition, a small number of reactive astrocytes revealed nuclear expression of 8-hydroxy-d-guanosine. Similarly, lipid peroxidation-derived structures (malondialdehyde and oxidized phospholipid epitopes) were seen in the cytoplasm of oligodendrocytes and some astrocytes. In addition, oxidized phospholipids were massively accumulated in a fraction of axonal spheroids with disturbed fast axonal transport as well as in neurons within grey matter lesions. Neurons stained for oxidized phospholipids frequently revealed signs of degeneration with fragmentation of their dendritic processes. The extent of lipid and DNA oxidation correlated significantly with inflammation, determined by the number of CD3 positive T cells and human leucocyte antigen-D expressing macrophages and microglia in the lesions. Our data suggest profound oxidative injury of oligodendrocytes and neurons to be associated with active demyelination and axonal or neuronal injury in multiple sclerosis.
611 citations
TL;DR: It is shown that the expression of α-synuclein in mammalian cells, including neurons in vitro and in vivo, causes the fragmentation of mitochondria.
523 citations
TL;DR: Inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves, as shown in the case of Parkinson’s disease and AD.
Abstract: Activation of microglia and inflammation-mediated neurotoxicity are suggested to play a decisive role in the pathogenesis of several neurodegenerative disorders. Activated microglia release pro-inflammatory factors that may be neurotoxic. Here we show that the orderly activation of caspase-8 and caspase-3/7, known executioners of apoptotic cell death, regulate microglia activation through a protein kinase C (PKC)-d-dependent pathway. We find that stimulation of microglia with various inflammogens activates caspase-8 and caspase-3/7 in microglia without triggering cell death in vitro and in vivo. Knockdown or chemical inhibition of each of these caspases hindered microglia activation and consequently reduced neurotoxicity. We observe that these caspases are activated in microglia in the ventral mesencephalon of Parkinson’s disease (PD) and the frontal cortex of individuals with Alzheimer’s disease (AD). Taken together, we show that caspase-8 and caspase-3/7 are involved in regulating microglia activation. We conclude that inhibition of these caspases could be neuroprotective by targeting the microglia rather than the neurons themselves. Numerous in vivo clinical imaging and neuropathology studies suggest that activated microglia, the resident immune cells of the central nervous system, play prominent roles in the pathogenesis of neurodegenerative disorders, including PD, multiple sclerosis and AD 1,2 . Microglia are necessary for normal brain function; however, uncontrolled and over-activated microglia can trigger neurotoxicity. They are a prominent source of pro-inflammatory factors and oxidative stress such as tumour-necrosis factor (TNF)-a, nitric oxide and interleukin (IL)-1b, which are neurotoxic 2,3 . Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia 1 . Intracerebral delivery of lipopolysaccharide (LPS), the major component of Gram-negative bacterial walls and a ligand for TLR4, leads in vivo to microglia activation and neuronal injury, and is used as model for brain inflammation 4,5 . Synergistic effects between interferon-c (IFN-c) and several TLR ligands (including TLR4) have been suggested, suggesting crosstalk between these pro-inflammatory receptor signalling pathways 6 . Furthermore, IFN-c receptor-deficient mice are less susceptible to LPS-induced endotoxic shock than control mice 7 . Finally, TLR4 has been implicated in AD pathophysiology in several contexts. Thus, the upregulation of cytokines is TLR4 dependent in an AD mouse model 8 ; certain TLR4 single nucleotide polymorphisms are associated with increased risk for AD 9 ; the levels of TLR4 messenger RNA (mRNA) are upregulated in APP transgenic mice 10 ; and increased TLR4 expression is associated with amyloid plaque deposition in AD brain tissue 10 . Caspases, a family of cysteinyl-aspartate-specific proteases, are executioners of apoptotic cell death and their activation is considered a commitment to cell death 11,12 . Certain caspases, for example caspase-1, also play a pivotal role in immune-mediated inflammation. In this situation, caspase activation is associated with the maturation of pro-inflammatory cytokines, such as IL-1b, IL-18, IL-33, and not with apoptosis 13 . Inhibition of caspase activation protects against neuronal loss in several animal models of brain diseases involving activated microglia, including hypoxic ischaemia/stroke, acute bacterial meningitis, brain trauma and 6-hydroxydopamine and 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonism models 2,14–17 . Currently, it is unclear whether inhibition of caspase activation specifically in microglia contributes to the neuroprotective effects of caspase inhibitors. We have now discovered that microglial activation in cell and animal models of inflammation involves caspases and that inhibition of the cascade in microglia prevents neurodegeneration. Furthermore, we demonstrate that caspase activation occurs in microglia in the brains of individuals with PD and AD, and thereby we validate the observations we made in relevant cell and animal models.
516 citations
TL;DR: These new mechanisms by which mitochondria may also be linked to neurodegeneration will likely have far-reaching implications for the understanding of the pathophysiology and treatment of adult-onset neuro degenerative disorders.
TL;DR: The results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures, but found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.
Abstract: Increasing evidence suggests that the accumulation of amyloid beta (Aβ) in synapses and synaptic mitochondria causes synaptic mitochondrial failure and synaptic degeneration in Alzheimer's disease (AD). The purpose of this study was to better understand the effects of Aβ in mitochondrial activity and synaptic alterations in neurons from a mouse model of AD. Using primary neurons from a well-characterized Aβ precursor protein transgenic (AβPP) mouse model (Tg2576 mouse line), for the first time, we studied mitochondrial activity, including axonal transport of mitochondria, mitochondrial dynamics, morphology and function. Further, we also studied the nature of Aβ-induced synaptic alterations, and cell death in primary neurons from Tg2576 mice, and we sought to determine whether the mitochondria-targeted antioxidant SS31 could mitigate the effects of oligomeric Aβ. We found significantly decreased anterograde mitochondrial movement, increased mitochondrial fission and decreased fusion, abnormal mitochondrial and synaptic proteins and defective mitochondrial function in primary neurons from AβPP mice compared with wild-type (WT) neurons. Transmission electron microscopy revealed a large number of small mitochondria and structurally damaged mitochondria, with broken cristae in AβPP primary neurons. We also found an increased accumulation of oligomeric Aβ and increased apoptotic neuronal death in the primary neurons from the AβPP mice relative to the WT neurons. Our results revealed an accumulation of intraneuronal oligomeric Aβ, leading to mitochondrial and synaptic deficiencies, and ultimately causing neurodegeneration in AβPP cultures. However, we found that the mitochondria-targeted antioxidant SS31 restored mitochondrial transport and synaptic viability, and decreased the percentage of defective mitochondria, indicating that SS31 protects mitochondria and synapses from Aβ toxicity.
TL;DR: This work finds a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease, and identifies a previously unknown casp enzyme-3–dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's Disease.
Abstract: Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's disease; however, the molecular mechanisms underlying synaptic failure are unknown. We found a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease. In spines, caspase-3 activated calcineurin, which in turn triggered dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. These molecular modifications led to alterations of glutamatergic synaptic transmission and plasticity and correlated with spine degeneration and a deficit in hippocampal-dependent memory. Notably, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued the observed Alzheimer-like phenotypes. Our results identify a previously unknown caspase-3-dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's disease. These findings indicate that caspase-3 is a potential target for pharmacological therapy during early disease stages.
TL;DR: The molecular mechanisms underlying the neuroprotective effects of rapamycin are reviewed and the therapeutic potential of this compound for neurodegenerative diseases is discussed.
Abstract: A growing number of studies point to rapamycin as a pharmacological compound that is able to provide neuroprotection in several experimental models of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease and spinocerebellar ataxia type 3. In addition, rapamycin exerts strong anti-ageing effects in several species, including mammals. By inhibiting the activity of mammalian target of rapamycin (mTOR), rapamycin influences a variety of essential cellular processes, such as cell growth and proliferation, protein synthesis and autophagy. Here, we review the molecular mechanisms underlying the neuroprotective effects of rapamycin and discuss the therapeutic potential of this compound for neurodegenerative diseases.
TL;DR: It is shown that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington’s disease in vivo before the presence of neurological deficits and huntingtin aggregates.
Abstract: Huntington's disease is an inherited and incurable neurodegenerative disorder caused by an abnormal polyglutamine (polyQ) expansion in huntingtin (encoded by HTT). PolyQ length determines disease onset and severity, with a longer expansion causing earlier onset. The mechanisms of mutant huntingtin-mediated neurotoxicity remain unclear; however, mitochondrial dysfunction is a key event in Huntington's disease pathogenesis. Here we tested whether mutant huntingtin impairs the mitochondrial fission-fusion balance and thereby causes neuronal injury. We show that mutant huntingtin triggers mitochondrial fragmentation in rat neurons and fibroblasts of individuals with Huntington's disease in vitro and in a mouse model of Huntington's disease in vivo before the presence of neurological deficits and huntingtin aggregates. Mutant huntingtin abnormally interacts with the mitochondrial fission GTPase dynamin-related protein-1 (DRP1) in mice and humans with Huntington's disease, which, in turn, stimulates its enzymatic activity. Mutant huntingtin-mediated mitochondrial fragmentation, defects in anterograde and retrograde mitochondrial transport and neuronal cell death are all rescued by reducing DRP1 GTPase activity with the dominant-negative DRP1 K38A mutant. Thus, DRP1 might represent a new therapeutic target to combat neurodegeneration in Huntington's disease.
TL;DR: It is reported that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies.
Abstract: The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway. This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.
TL;DR: Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life, but further studies are needed to clarify the relative contribution of glucOCorticoids and inflammatory signals to MD.
Abstract: Major depression (MD) is a common psychiatric disorder with a complex and multifactor aetiology. Potential mechanisms associated with the pathogenesis of this disorder include monoamine deficits, hypothalamic-pituitary-adrenal (HPA) axis dysfunctions, inflammatory and/or neurodegenerative alterations. An increased secretion and reactivity of cortisol together with an altered feedback inhibition are the most widely observed HPA abnormalities in MD patients. Glucocorticoids, such as cortisol, are vital hormones that are released in response to stress, and regulate metabolism and immunity but also neuronal survival and neurogenesis. Interestingly depression is highly prevalent in infectious, autoimmune and neurodegenerative diseases and at the same time, depressed patients show higher levels of pro-inflammatory cytokines. Since communication occurs between the endocrine, immune and central nervous system, an activation of the inflammatory responses can affect neuroendocrine processes, and vice versa. Therefore, HPA axis hyperactivity and inflammation might be part of the same pathophysiological process: HPA axis hyperactivity is a marker of glucocorticoid resistance, implying ineffective action of glucocorticoid hormones on target tissues, which could lead to immune activation; and, equally, inflammation could stimulate HPA axis activity via both a direct action of cytokines on the brain and by inducing glucocorticoid resistance. In addition, increased levels of pro-inflammatory cytokines also induce the production of neurotoxic end products of the tryptophan-kynurenine pathway. Although the evidence for neurodegeneration in MD is controversial, depression is co-morbid with many other conditions where neurodegeneration is present. Since several systems seem to be involved interacting with each other, we cannot unequivocally accept the simple model that glucocorticoids induce neurodegeneration, but rather that elevated cytokines, in the context of glucocorticoid resistance, are probably the offenders. Chronic inflammatory changes in the presence of glucocorticoid resistance may represent a common feature that could be responsible for the enhanced vulnerability of depressed patients to develop neurodegenerative changes later in life. However, further studies are needed to clarify the relative contribution of glucocorticoids and inflammatory signals to MD and other disorders.
TL;DR: In this paper, the authors revisited the hypothesis that advanced glycation endproducts (AGEs) and their receptor RAGE may play an important role in disease pathogenesis by influencing transport of β-amyloid into the brain or by manipulating inflammatory mechanisms.
TL;DR: Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain, and it extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease.
TL;DR: Investigation of the brain insulin–PI3K–AKT signalling pathway in autopsied frontal cortices provides novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.
Abstract: Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.
TL;DR: This model represents a new experimental system to identify compounds that reduce levels of α- synuclein, and to investigate the mechanistic basis of neurodegeneration caused by α-synuclein dysfunction.
Abstract: Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.
TL;DR: Assessment of glial changes in Parkinson's disease at the time of disease initiation when α‐synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident.
Abstract: Background:
Glia are traditionally known as support cells for neurons, and their role in neurodegeneration has been largely considered secondary to neuronal dysfunction. We review newer concepts on glial function and assess glial changes in Parkinson's disease (PD) at the time of disease initiation when α-synuclein is accumulating in brain tissue but there is limited neuronal loss, and also as the disease progresses and neuronal loss is evident.
Results:
Of the two main types of astrocytes, only protoplasmic astrocytes are involved in PD, where they become nonreactive and accumulate α-synuclein. Experimental evidence has shown that astrocytic α-synuclein deposition initiates the noncell autonomous killing of neurons through microglial signaling. As the disease progresses, more protoplasmic astrocytes are affected by the disease with an increasing microglial response. Although there is still controversy on the role microglia play in neurodegeneration, there is evidence that microglia are activated early in PD and possibly assist with the clearance of extracellular α-synuclein at this time. Microglia transform to phagocytes and target neurons as the disease progresses but appear to become dysfunctional with increasing amounts of ingested debris. Only nonmyelinating oligodendroglial cells are affected in PD, and only late in the disease process.
Conclusions:
Glial cells are responsible for the progression of PD and play an important role in initiating the early tissue response. In particular, early dysfunction and α-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons in restricted brain regions causing the clinical symptoms of PD. © 2011 Movement Disorder Society
TL;DR: It seems evident that targeting adenosine receptors might indeed constitute a novel strategy to control the demise of different neurological and psychiatric disorders.
TL;DR: It is reported that chronic dosing of 3xTg-AD mice with an IL-1R blocking Ab significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β.
Abstract: Inflammation is a key pathological hallmark of Alzheimer’s disease (AD), although its impact on disease progression and neurodegeneration remains an area of active investigation. Among numerous inflammatory cytokines associated with AD, IL-1β in particular has been implicated in playing a pathogenic role. In this study, we sought to investigate whether inhibition of IL-1β signaling provides disease-modifying benefits in an AD mouse model and, if so, by what molecular mechanisms. We report that chronic dosing of 3xTg-AD mice with an IL-1R blocking Ab significantly alters brain inflammatory responses, alleviates cognitive deficits, markedly attenuates tau pathology, and partly reduces certain fibrillar and oligomeric forms of amyloid-β. Alterations in inflammatory responses correspond to reduced NF-κB activity. Furthermore, inhibition of IL-1 signaling reduces the activity of several tau kinases in the brain, including cdk5/p25, GSK-3β, and p38–MAPK, and also reduces phosphorylated tau levels. We also detected a reduction in the astrocyte-derived cytokine, S100B, and in the extent of neuronal Wnt/β-catenin signaling in 3xTg-AD brains, and provided in vitro evidence that these changes may, in part, provide a mechanistic link between IL-1 signaling and GSK-3β activation. Taken together, our results suggest that the IL-1 signaling cascade may be involved in one of the key disease mechanisms for AD.
TL;DR: This study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner, and will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD.
Abstract: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant familial Parkinson's disease (PD) and also contribute to idiopathic PD. LRRK2 mutations represent the most common cause of PD with clinical and neurochemical features that are largely indistinguishable from idiopathic disease. Currently, transgenic mice expressing wild-type or disease-causing mutants of LRRK2 have failed to produce overt neurodegeneration, although abnormalities in nigrostriatal dopaminergic neurotransmission have been observed. Here, we describe the development and characterization of transgenic mice expressing human LRRK2 bearing the familial PD mutations, R1441C and G2019S. Our study demonstrates that expression of G2019S mutant LRRK2 induces the degeneration of nigrostriatal pathway dopaminergic neurons in an age-dependent manner. In addition, we observe autophagic and mitochondrial abnormalities in the brains of aged G2019S LRRK2 mice and markedly reduced neurite complexity of cultured dopaminergic neurons. These new LRRK2 transgenic mice will provide important tools for understanding the mechanism(s) through which familial mutations precipitate neuronal degeneration and PD.
TL;DR: It is proposed that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in the yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
Abstract: Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of these genes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having a more severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.
TL;DR: Results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques and suggesting that reactive glia might contribute to the ongoing neurodegeneration.
Abstract: Senile plaques are a prominent pathological feature of Alzheimer's disease (AD), but little is understood about the association of glial cells with plaques or about the dynamics of glial responses through the disease course. We investigated the progression of reactive glial cells and their relationship with AD pathological hallmarks to test whether glial cells are linked only to amyloid deposits or also to tangle deposition, thus integrating both lesions as a marker of disease severity. We conducted a quantitative stereology-based post-mortem study on the temporal neocortex of 15 control subjects without dementia and 91 patients with AD, including measures of amyloid load, neurofibrillary tangles, reactive astrocytes, and activated microglia. We also addressed the progression of glial responses in the vicinity (≤50 μm) of dense-core plaques and tangles. Although the amyloid load reached a plateau early after symptom onset, astrocytosis and microgliosis increased linearly throughout the disease course. Moreover, glial responses correlated positively with tangle burden, whereas astrocytosis correlated negatively with cortical thickness. However, neither correlated with amyloid load. Glial responses increased linearly around existing plaques and in the vicinity of tangles. These results indicate that the progression of astrocytosis and microgliosis diverges from that of amyloid deposition, arguing against a straightforward relationship between glial cells and plaques. They also suggest that reactive glia might contribute to the ongoing neurodegeneration.
TL;DR: Interestingly, recent animal studies have also indicated that complement activation products are involved in brain development and synapse formation, which may give insights into the role of complement in processes of neurodegeneration and neuroprotection in the injured or aged and diseased adult central nervous system, and thus aid in identifying novel and specific targets for therapeutic intervention.
TL;DR: The data suggest that perturbation of endogenous nuclear TDP-43 results in loss of normal T DP-43 function(s) and gene regulatory pathways, culminating in degeneration of selectively vulnerable affected neurons.
Abstract: Fil: Muller Igaz, Lionel Ivan. University of Pennsylvania; Estados Unidos. Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Houssay; Argentina
TL;DR: This special issue is composed of 9 excellent reviews and 3 distinguished original articles that summarize the most recent progresses and ideas obtained from animal models in the pertinent field, while reporting the putative molecular mechanisms of neurodegeneration, therapeutic challenges and limitations using PD models, and generation of new versions of PD models.
Abstract: Parkinson's disease (PD) is considered a multifactorial disorder, which is neuropathologically characterized by age-dependent neurodegeneration of dopaminergic neurons in the midbrain. Different neurotoxins including synthetic compounds, heavy metals, and dopamine itself have been proposed to be environmental risk factors of PD. Recent genome-wide genetic and mutational studies provide information on various genetic risk factors while microglial activation in the affected regions has emerged to be involved in the disease development as a local microenvironmental factor. A wide variety of animal models of PD substantially contribute to the understanding of these issues and the development of therapeutic approaches as an alternative to humans although none of them fully recaptures the symptoms and pathology of PD. This special issue is composed of 9 excellent reviews and 3 distinguished original articles that summarize the most recent progresses and ideas obtained from animal models in the pertinent field, while reporting the putative molecular mechanisms of neurodegeneration, therapeutic challenges and limitations using PD models, and generation of new versions of PD models.
The first review paper briefly outlines animal models of PD, covering toxin-induced and genetic models of vertebrate and invertebrate animals, in which characteristic features of each model are discussed.
Mishandling of monoamines including dopamine has been hypothesized to damage neurons. The second review paper describes mice with impaired functions of the vesicular monoamine transporter VMAT2, in which progressive loss of catecholamine-secreting neurons is observed. Such models may be potentially useful for the development of new therapeutic strategies, which would complement current dopamine replacement.
Neuropathological analysis of the postmortem PD brain tissues suggests that an adverse interaction with surrounding glia and other nonneuronal cells may be one of critical steps in neurodegeneration. The third review highlights endotoxin-induced inflammation models, in which activation of microglia and lymphocyte by a bacterial lipopolysaccharide deteriorates a healthy relationship with neurons.
Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified to cause autosomal-dominant late-onset PD and are also implicated in sporadic PD. The neuropathological features of PD brain tissues with the LRRK2 mutations are characterized by typical Lewy body pathology in the brainstem. The forth paper reviews a variety of LRRK2-related models.
Mutations and increased expression in the α-synuclein gene cause the development of early-onset familial PD. The formation of α-synuclein fibrils and aggregates, a main component of Lewy bodies and Lewy neurites, is considered a key process in the pathogenesis of PD and other synucleinophathies. Other genetic determinants include the genes for Mendelian forms of PD and susceptible genes. The following two papers focus on the potential of Drosophila genetic models to examine α-synuclein and other responsible genes.
Deep brain stimulation (DBS) by electrical pulses could be one of useful therapeutic avenues for PD. However, DBS's technique requires advancement and poor understanding of the mechanisms involved hinder application in clinical practice. The seventh review paper discusses the optimization of a rat PD model for DBS.
Hydrogen has turned out to reduce oxidative damage. The eighth paper introduces the neuroprotective effects of hydrogen on experimental animal models for PD and possible application in treatment and prevention of PD.
The last review explains the limitations of animal models, showing differences between humans and animals, and difficulties in interpretation of obtained results with animal models.
The first research paper investigates selective degeneration of dopaminergic neurons in the substantia nigra and associated motor dysfunction induced by inhalation of mixed manganese compounds on mice. This model could be instrumental for evaluating some aspects of a progressive loss of dopaminergic neurons. The second research paper examines the possible effects of testosterone on PD using a mouse model induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. The study suggests that loss of testosterone induces remodeling in the morphology of medium spiny neurons where dopaminergic neurons of the substantia nigra project although no interaction between testosterone and loss of dopaminergic neurons by MPTP administration is observed. The third research paper of this special issue addresses improvement of potential gene therapy to compensate for impaired complex I activity of the mitochondria using the yeast single-subunit NADH-ubiquinone oxidoreductase, NDI1. NDI1 is functionally able to replace complex I, activity of which is thought to be compromised in most of PD cases.
A decreased sense of smell is one of early signs of PD. Although degeneration of tyrosine hydroxylase-positive neurons in the olfactory bulbs is observed, the pathogenic mechanism underlying olfactory deficits is not well understood. The forth research paper addresses this issue using a rat model bearing the pathogenic α-synuclein.
Yuzuru Imai
Katerina Venderova
David S. Park
Huaibin Cai
Enrico Schmidt