Dysfunction In Neurodegenerative Diseases Research Articles

Social Cognition Dysfunctions in Neurodegenerative Diseases: Neuroanatomical Correlates and Clinical Implications.

Social cognitive function, involved in the perception, processing, and interpretation of social information, has been shown to be crucial for successful communication and interpersonal relationships, thereby significantly impacting mental health, well-being, and quality of life. In this regard, assessment of social cognition, mainly focusing on four key domains, such as theory of mind (ToM), emotional empathy, and social perception and behavior, has been increasingly evaluated in clinical settings, given the potential implications of impairments of these skills for therapeutic decision-making. With regard to neurodegenerative diseases (NDs), most disorders, characterized by variable disease phenotypes and progression, although similar for the unfavorable prognosis, are associated to impairments of social cognitive function, with consequent negative effects on patients' management. Specifically, in some NDs these deficits may represent core diagnostic criteria, such as for behavioral variant frontotemporal dementia (bvFTD), or may emerge during the disease course as critical aspects, such as for Parkinson's and Alzheimer's diseases. On this background, we aimed to revise the most updated evidence on the neurobiological hypotheses derived from network-based approaches, clinical manifestations, and assessment tools of social cognitive dysfunctions in NDs, also prospecting potential benefits on patients' well-being, quality of life, and outcome derived from potential therapeutic perspectives of these deficits.

Correction: Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases.

Vol. 216, No. 12, December 4, 2017. [10.1083/jcb.201709172][1]. In the section Mitochondrial Aβ and OXPHOS in AD, this review cites one study (Cenini et al., 2016) in a statement that does not correctly represent the findings. Therefore, the authors wish to correct the statement to more accurately

Proteinopathies and OXPHOS dysfunction in neurodegenerative diseases.

Mitochondria participate in essential processes in the nervous system such as energy and intermediate metabolism, calcium homeostasis, and apoptosis. Major neurodegenerative diseases are characterized pathologically by accumulation of misfolded proteins as a result of gene mutations or abnormal protein homeostasis. Misfolded proteins associate with mitochondria, forming oligomeric and fibrillary aggregates. As mitochondrial dysfunction, particularly of the oxidative phosphorylation system (OXPHOS), occurs in neurodegeneration, it is postulated that such defects are caused by the accumulation of misfolded proteins. However, this hypothesis and the pathological role of proteinopathies in mitochondria remain elusive. In this study, we critically review the proposed mechanisms whereby exemplary misfolded proteins associate with mitochondria and their consequences on OXPHOS.

Synaptic Activity Protects Neurons Against Calcium-Mediated Oxidation and Contraction of Mitochondria During Excitotoxicity.

Excitotoxicity triggered by extrasynaptic N-methyl-d-aspartate-type glutamate receptors has been implicated in many neurodegenerative conditions, including Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Mitochondrial calcium overload leading to mitochondrial dysfunction represents an early event in excitotoxicity. Neurons are rendered resistant to excitotoxicity by previous periods of synaptic activity that activates a nuclear calcium-driven neuroprotective gene program. This process, termed acquired neuroprotection, involves transcriptional repression of the mitochondrial calcium uniporter leading to a reduction in excitotoxcity-associated mitochondrial calcium load. As mitochondrial calcium and the production of reactive oxygen species may be linked, we monitored excitotoxicity-associated changes in the mitochondrial redox status using the ratiometric glutathione redox potential indicator, glutaredoxin 1 (GRX1)-redox-sensitive green fluorescent protein (roGFP)2, targeted to the mitochondrial matrix. Aim of this study was to investigate if suppression of oxidative stress underlies mitoprotection afforded by synaptic activity. We found that synaptic activity protects primary rat hippocampal neurons against acute excitotoxicity-induced mitochondrial oxidative stress and mitochondrial contraction associated with it. Downregulation of the mitochondrial uniporter by genetic means mimics the protective effect of synaptic activity on mitochondrial redox status. These findings indicate that oxidative stress acts downstream of mitochondrial calcium overload in excitotoxicity. Innovation and Conclusion: We established mito-GRX1-roGFP2 as a reliable and sensitive tool to monitor rapid redox changes in mitochondria during excitotoxicity. Our results highlight the importance of developing means of blocking mitochondrial calcium overload for therapeutic targeting of oxidative stress and mitochondrial dysfunction in neurodegenerative diseases. Antioxid. Redox. Signal. 29, 1109-1124.

Multimodal correlation of dynamic [18F]-AV-1451 perfusion PET and neuronal hypometabolism in [18F]-FDG PET

Cerebral glucose metabolism measured with [18F]-FDG PET is a well established marker of neuronal dysfunction in neurodegeneration. The tau-protein tracer [18F]-AV-1451 PET is currently under evaluation and shows promising results. Here, we assess the feasibility of early perfusion imaging with AV-1451 as a substite for FDG PET in assessing neuronal injury. Twenty patients with suspected neurodegeneration underwent FDG and early phase AV-1451 PET imaging. Ten one-minute timeframes were acquired after application of 200MBq AV-1451. FDG images were acquired on a different date according to clinical protocol. Early AV-1451 timeframes were coregistered to individual FDG-scans and spatially normalized. Voxel-wise intermodal correlations were calculated on within-subject level for every possible time window. The window with highest pooled correlation was considered optimal. Z-transformed deviation maps (ZMs) were created from both FDG and early AV-1451 images, comparing against FDG images of healthy controls. Regional patterns and extent of perfusion deficits were highly comparable to metabolic deficits. Best results were observed in a time window from 60 to 360s (r=0.86). Correlation strength ranged from r=0.96 (subcortical gray matter) to 0.83 (frontal lobe) in regional analysis. ZMs of early AV-1451 and FDG images were highly similar. Perfusion imaging with AV-1451 is a valid biomarker for assessment of neuronal dysfunction in neurodegenerative diseases. Radiation exposure and complexity of the diagnostic workup could be reduced significantly by routine acquisition of early AV-1451 images, sparing additional FDG PET.

Pet neuroimaging for oxidative stress based on mitochondrial dysfunction in Neurodegenerative Diseases

Pet neuroimaging for oxidative stress based on mitochondrial dysfunction in Neurodegenerative Diseases

The impact of scopolamine pretreatment on 3-iodothyronamine (T1AM) effects on memory and pain in mice

We previously demonstrated that 3-iodothyronamine (T1AM), a by-product of thyroid hormone metabolism, pharmacologically administered to mice acutely stimulated learning and memory acquisition and provided hyperalgesia with a mechanism which remains to be defined. We now aimed to investigate whether the T1AM effect on memory and pain was maintained in mice pre-treated with scopolamine, a non-selective muscarinic antagonist expected to induce amnesia and, possibly, hyperalgesia.Mice were pre-treated with scopolamine and, after 20min, injected intracerebroventricularly (i.c.v.) with T1AM (0.13, 0.4, 1.32μg/kg). 15min after T1AM injection, the mice learning capacity or their pain threshold were evaluated by the light/dark box and by the hot plate test (51.5°C) respectively. Experiments in the light/dark box were repeated in mice receiving clorgyline (2.5mg/kg, i.p.), a monoamine oxidase (MAO) inhibitor administered 10min before scopolamine (0.3mg/kg).Our results demonstrated that 0.3mg/kg scopolamine induced amnesia without modifying the murine pain threshold. T1AM fully reversed scopolamine-induced amnesia and produced hyperalgesia at a dose as low as 0.13μg/kg. The T1AM anti-amnestic effect was lost in mice pre-treated with clorgyline.We report that the removal of muscarinic signalling increases T1AM pro learning and hyperalgesic effectiveness suggesting T1AM as a potential treatment as a “pro-drug” for memory dysfunction in neurodegenerative diseases.

Lysosomal dysfunction in neurodegenerative diseases.

Dane literaturowe z ostatnich lat jednoznacznie wskazują na udział lizosomów w programowanej śmierci komórki. Dysfunkcje lizosomów upośledzają fuzję autofagosomów z lizosomami, co prowadzi do wakuolizacji cytoplazmy. Obecność wakuoli autofagalnych obładowanych uszkodzonymi organellami i nieprawidłowymi białkami jest cechą charakterystyczną wielu chorób neurodegeneracyjnych. Agregacja niezdegradowanego materiału zaburza homeostazę komórki powodując śmierć neuronu w wyniku apoptozy i/lub nekrozy. Ponadto indukowany kalpainami lub spowodowany mutacjami rozpad błony lizosomu uwalnia katepsyny, które indukują szlak śmierci komórki. W artykule przedstawiono mechanizm śmierci komórki nerwowej, łączący zaburzenie szlaku autofagalno-lizosomalnego z dysfunkcjami lizosomów, zwany lizosomalnym szlakiem śmierci neuronu.

Reduced emotional sensitivity and responsiveness measured by the Revised Self-Monitoring Scale is a behavioral marker of early salience network dysfunction in neurodegenerative disease (S35.005)

Reduced emotional sensitivity and responsiveness measured by the Revised Self-Monitoring Scale is a behavioral marker of early salience network dysfunction in neurodegenerative disease (S35.005)

Synaptic Plasticity, Dementia and Alzheimer Disease.

Neuroplasticity is not only shaped by learning and memory but is also a mediator of responses to neuron attrition and injury (compensatory plasticity). As an ongoing process it reacts to neuronal cell activity and injury, death, and genesis, which encompasses the modulation of structural and functional processes of axons, dendrites, and synapses. The range of structural elements that comprise plasticity includes long-term potentiation (a cellular correlate of learning and memory), synaptic efficacy and remodelling, synaptogenesis, axonal sprouting and dendritic remodelling, and neurogenesis and recruitment. Degenerative diseases of the human brain continue to pose one of biomedicine's most intractable problems. Research on human neurodegeneration is now moving from descriptive to mechanistic analyses. At the same time, it is increasing apparently that morphological lesions traditionally used by neuropathologists to confirm post-mortem clinical diagnosis might furnish us with an experimentally tractable handle to understand causative pathways. Consider the aging-dependent neurodegenerative disorder Alzheimer's disease (AD) which is characterised at the neuropathological level by deposits of insoluble amyloid β-peptide (Aβ) in extracellular plaques and aggregated tau protein, which is found largely in the intracellular neurofibrillary tangles. We now appreciate that mild cognitive impairment in early AD may be due to synaptic dysfunction caused by accumulation of non-fibrillar, oligomeric Aβ, occurring well in advance of evident widespread synaptic loss and neurodegeneration. Soluble Aβ oligomers can adversely affect synaptic structure and plasticity at extremely low concentrations, although the molecular substrates by which synaptic memory mechanisms are disrupted remain to be fully elucidated. The dendritic spine constitutes a primary locus of excitatory synaptic transmission in the mammalian central nervous system. These structures protruding from dendritic shafts undergo dynamic changes in number, size and shape in response to variations in hormonal status, developmental stage, and changes in afferent input. It is perhaps not unexpected that loss of spine density may be linked to cognitive and memory impairment in AD, although the underlying mechanism(s) remain uncertain. This article aims to present a critical overview of current knowledge on the bases of synaptic dysfunction in neurodegenerative diseases, with a focus on AD, and will cover amyloid- and nonamyloid- driven mechanisms. We will consider also emerging data dealing with potential therapeutic approaches for ameliorating the cognitive and memory deficits associated with these disorders.

New Therapeutics to Modulate Mitochondrial Function in Neurodegenerative Disorders.

Mitochondrial function and energy metabolism are impaired in neurodegenerative diseases. There is evidence for these functional declines both within the brain and systemically in Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis. Due to these observations, therapeutics targeted to alter mitochondrial function and energy pathways are increasingly studied in pre-clinical and clinical settings. The goal of this article was to review therapies with specific implications on mitochondrial energy metabolism published through May 2016 that have been tested for treatment of neurodegenerative diseases. We discuss implications for mitochondrial dysfunction in neurodegenerative diseases and how this drives new therapeutic initiatives. Thus far, treatments have achieved varying degrees of success. Further investigation into the mechanisms driving mitochondrial dysfunction and bioenergetic failure in neurodegenerative diseases is warranted.

Neuronal Mitophagy in Neurodegenerative Diseases

Neuronal homeostasis depends on the proper functioning of different quality control systems. All intracellular components are subjected to continuous turnover through the coordinated synthesis, degradation and recycling of their constituent elements. Autophagy is the catabolic mechanism by which intracellular cytosolic components, including proteins, organelles, aggregates and any other intracellular materials, are delivered to lysosomes for degradation. Among the different types of selective autophagy described to date, the process of mitophagy involves the selective autophagic degradation of mitochondria. In this way, mitophagy is responsible for basal mitochondrial turnover, but can also be induced under certain physiological or pathogenic conditions to eliminate unwanted or damaged mitochondria. Dysfunctional cellular proteolytic systems have been linked extensively to neurodegenerative diseases (ND) like Alzheimer’s disease (AD), Parkinson’s disease (PD), or Huntington’s disease (HD), with autophagic failure being one of the main factors contributing to neuronal cell death in these diseases. Neurons are particularly vulnerable to autophagic impairment as well as to mitochondrial dysfunction, due mostly to their particular high energy dependence and to their post-mitotic nature. The accurate and proper degradation of dysfunctional mitochondria by mitophagy is essential for maintaining control over mitochondrial quality and quantity in neurons. In this report, I will review the role of mitophagy in neuronal homeostasis and the consequences of its dysfunction in ND.

Astroglial transcriptome dysregulation in early disease of an ALS mutant SOD1 mouse model

Astroglia are a morphologically diverse and highly abundant cell type in the CNS. Despite these obvious observations, astroglia still remain largely uncharacterized at the cellular and molecular level. In disease contexts such as amyotrophic lateral sclerosis (ALS), it has been widely shown that astroglia downregulate crucial physiological functions, become hypertrophied, reactive, and toxic to motor neurons. However, little is known about the astroglia-specific transcriptomic changes that occur during ALS disease progression, especially early in disease. To address this, we FACS-isolated pure astroglia from early and mid-symptomatic superoxide dismutase 1 (SOD1) G93A spinal cord and performed microarray sequencing, in hopes to uncover markers and pathways driving astroglia dysfunction in ALS. After extensive analyses, we uncovered genes selectively enriched and downregulated in both control and SOD1 astroglia at both disease points. In addition, we were able to identify genes and pathways differentially expressed that may have relevance with other neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, suggesting a common theme among astroglial dysfunction in neurodegenerative disease. In aggregate, this study sheds light on the common and unique themes of dysfunction that astroglia undergo during neurodegenerative disease progression and provides candidate targets for therapeutic approaches.

Development and Dynamic Regulation of Mitochondrial Network in Human Midbrain Dopaminergic Neurons Differentiated from iPSCs

SummaryMitochondria are critical to neurogenesis, but the mechanisms of mitochondria in neurogenesis have not been well explored. We fully characterized mitochondrial alterations and function in relation to the development of human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons. Following directed differentiation of hiPSCs to DA neurons, mitochondria in these neurons exhibit pronounced changes during differentiation, including mature neurophysiology characterization and functional synaptic network formation. Inhibition of mitochondrial respiratory chains via application of complex IV inhibitor KCN (potassium cyanide) or complex I inhibitor rotenone restricted neurogenesis of DA neurons. These results demonstrated the direct importance of mitochondrial development and bioenergetics in DA neuronal differentiation. Our study also provides a neurophysiologic model of mitochondrial involvement in neurogenesis, which will enhance our understanding of the role of mitochondrial dysfunctions in neurodegenerative diseases.

Targeting NO/cGMP Signaling in the CNS for Neurodegeneration and Alzheimer's Disease.

cAMP-response element-binding protein (CREB) plays a central role in various aspects of central nervous system (CNS) function, ranging from the developmental stages to neuronal plasticity and survival in adult brain. Activation of CREB plays a crucial role in learning and memory and is at the convergence of multiple intracellular signaling cascades including CAMKII and MAPK. This review focuses on the important functions of nitric oxide (NO) in activating CREB via the NO receptor, soluble guanylyl cyclase (sGC), and production of the second messenger, cGMP. The involvement of the NO/cGMP signaling pathway in synaptic plasticity suggests several avenues for therapeutic intervention, and targeting early synaptic degeneration could be an attractive approach for the development of novel disease-modifying approaches to treat cognition and memory dysfunction in neurodegenerative diseases.

Neuroprotective effects of Liriope platyphylla extract against hydrogen peroxide-induced cytotoxicity in human neuroblastoma SH-SY5Y cells.

BackgroundOxidative stress is involved in neuronal cell death and mitochondrial dysfunction in neurodegenerative diseases. Liriope platyphylla (LP) has been suggested to have anti-inflammation, anti-bacterial, and anti-cancer effects. However, whether LP exerts neuroprotective effects on neuronal cells is unknown.MethodsThe present study was performed to investigate the neuroprotective effects of LP extract (LPE) against hydrogen peroxide (H2O2)-induced injury in human neuroblastoma cells SH-SY5Y. To test neuroprotective effects of LPE, we performed cell viability assay, flow cytometry analysis and western blot analysis. In addition, mitochondrial membrane potential (MMP) and oxidative stress were performed to evaluate the anti-apoptotic and anti-oxidant effects.ResultsLPE pretreatment conferred significant protection against the H2O2-induced decrease of SH-SY5Y cell viability. H2O2-induced increases of intracellular oxidative stress and mitochondrial dysfunction were attenuated by LPE pretreatment. Therefore, LPE pretreatment prevented SH-SY5Y cell injury. Treatment with H2O2 significantly induced poly(ADP ribose) polymerase (PARP) and caspase-3 cleavage, which was blocked by LPE. We found that p38 activation was involved in the neuroprotective effects of LPE.ConclusionsCurrent findings suggest that LPE exerts neuroprotective effects against H2O2-induced apoptotic cell death by modulating p38 activation in SH-SY5Y cells. Therefore, LPE has potential anti-apoptotic effects that may be neuroprotective in neurodegenerative diseases and aging-related dementia.

Emotional dysfunctions in neurodegenerative diseases.

Neurodegenerative diseases are characterized primarily by motor signs but are also accompanied by emotional disturbances. Because of the limited knowledge about these dysfunctions, this Review provides an overview of emotional competencies in Huntington's disease (HD), Parkinson's disease (PD), and multiple sclerosis (MS), with a focus on emotion recognition, emotion regulation, and depression. Most studies indicate facial emotion recognition deficits in HD and PD, whereas data for MS are inconsistent. On a neural level, dysfunctions of amygdala and striatum, among others, have been linked to these impairments. These dysfunctions also tap brain regions that are part of the emotion regulation network, suggesting problems in this competency, too. Research points to dysfunctional emotion regulation in MS, whereas findings for PD and HD are missing. The high prevalence of depression in all three disorders emphasizes the need for effective therapies. Research on emotional disturbances might improve treatment, thereby increasing patients' and caregivers' well-being.

A spotlight on microneurotrophins: the future of amyotrophic lateral sclerosis treatment?

James P Bennett Jr* speaks to Daphne Boulicault, Commissioning Editor: James P Bennett, Jr is a native of St Petersburg, FL, USA. He received a BS in chemistry (with Honors) from the University of Florida (1970), then attended Johns Hopkins University School of Medicine for his MD (1974) and PhD (pharmacology, 1977) degrees. He worked in the laboratory of Dr Solomon Snyder, MD, for 6 years while in medical and graduate schools and trained in neuropharmocology. He then trained clinically for 2 years in internal medicine (1978–1980), followed by Neurology residency at the University of Virginia (UVA; 1980–1983) where he was Chief Resident (1982–1983). He became a faculty member in the UVA Departments of Neurology, Psychiatry and Pharmacology (1983–2009) and held the Ebbert Chair in Medical Science. In 2009, he moved to Virginia Commonwealth University, where he is the Bemiss Professor, was Chair of Neurology (2009–2013) and is founding Director of the Parkinson’s Disease and Movement Disorder Center (2009–2015). He has held multiple NIH grants and directed the NIH-funded Udall Parkinson’s Center at UVA. He investigates mitochondrial dysfunction in adult neurodegenerative diseases. He holds multiple patents related to experimental therapies of degenerative disorders.

Lysosomal dysfunction in neurodegenerative diseases

Lysosomal dysfunction in neurodegenerative diseases

Combination of PPT with LiCl Treatment Prevented Bilateral Ovariectomy-Induced Hippocampal-Dependent Cognition Deficit in Rats.

Estrogen deprivation is a high risk of cognitive dysfunction in neurodegenerative diseases, and the early used estrogen replacement has been proved effective in many studies. Because of the adverse actions, selective estrogen receptor modulating has been raised to substitute for estrogen replacement. In this study, we observed in hippocampus of bilaterally ovariectomized rats that the level of estrogen receptor α (ERα) was decreased in nuclei with activated glycogen synthase kinase-3β (GSK-3β) in cytoplasm at 8 weeks after operation. The level of nuclear ERα is important for its transcriptional property, and the inhibition of GSK-3β benefits to ERα nuclear translocation. Then, we used 4,4k,4a-(4-propyl-[1H]-pyrazole-1, 3, 5-triyl) trisphenol (PPT) (1 mg/kg/day), an agonist of ERα, combined with LiCl (40 mg/kg/day), an inhibitor of GSK-3β, to treat the ovariectomized rats. After the combination treatment of these two drugs (PPT + LiCl), the improved learning and memory abilities of ovariectomized rats in Morris water maze, increased dendritic spines in CA1 region, and decreased tau phosphorylation at Ser-396 in hippocampus were observed. Furthermore, PPT + LiCl treatment significantly increased ERα level in the nuclear fraction of hippocampus, and in the cytoplasmic fraction, the total level of GSK-3β was declined after treatment with its increased phosphorylation at Ser-9 (inactivation form). This study suggested that PPT + LiCl treatment could inhibit the activation of cytoplasmic GSK-3β and promote the nuclear translocation of ERα, and ERα together with GSK-3β maybe the targets to preserve hippocampus-dependent cognitive ability after long-term ovariectomy.