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Nath, Sangeeta
Publications (6 of 6) Show all publications
Helmfors, L., Boman, A., Civitelli, L., Nath, S., Sandin, L., Janefjord, C., . . . Kågedal, K. (2015). Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease. Neurobiology of Disease, 83, 122-133
Open this publication in new window or tab >>Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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2015 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, p. 122-133Article in journal (Refereed) Published
Abstract [en]

The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, Aβ aggregation
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122341 (URN)10.1016/j.nbd.2015.08.024 (DOI)000366230000012 ()26334479 (PubMedID)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2018-01-10Bibliographically approved
Agholme, L., Nath, S., Domert, J., Marcusson, J., Kågedal, K. & Hallbeck, M. (2014). Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease. Molecular and Cellular Neuroscience, 58, 29-39
Open this publication in new window or tab >>Proteasome Inhibition Induces Stress Kinase Dependent Transport Deficits – Implications for Alzheimer’s Disease
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2014 (English)In: Molecular and Cellular Neuroscience, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 58, p. 29-39Article in journal (Refereed) Published
Abstract [en]

Alzheimer’s disease (AD) is characterized by accumulation of two misfolded and aggregated proteins, β-amyloid and hyperphosphorylated tau. Both cellular systems responsible for clearance of misfolded and aggregated proteins, the lysosomal and the proteasomal, have been shown to be malfunctioning in the aged brain and more so in AD patients. This malfunction could be the cause of β-amyloid and tau accumulation, eventually aggregating in plaques and tangles. We have investigated how decreased proteasome activity affects AD related pathophysiological changes of microtubule transport and stability, as well as tau phosphorylation. To do this, we used our recently developed neuronal model where human SH-SY5Y cells obtain neuronal morphology and function through differentiation. We found that exposure to low doses of the proteasome inhibitor MG-115 caused disturbed neuritic transport, together with microtubule destabilization and tau phosphorylation. Furthermore, reduced proteasome activity activated several kinases implicated in AD pathology, including JNK, c-Jun and ERK 1/2. Restoration of the microtubule transport was achieved by inhibiting ERK 1/2 activation, and simultaneous inhibition of both ERK 1/2 and c-Jun reversed the proteasome inhibition-induced tau phosphorylation. Taken together, this study suggests that a decrease in proteasome activity can, through activation of c-Jun and ERK 1/2, result in several events contributing to AD pathology. Restoring proteasome function or inhibiting ERK 1/2 and c-Jun could therefore be used as novel treatments against AD.

Place, publisher, year, edition, pages
Elsevier, 2014
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-81339 (URN)10.1016/j.mcn.2013.11.001 (DOI)000331853600004 ()
Available from: 2012-09-12 Created: 2012-09-12 Last updated: 2019-10-14Bibliographically approved
Domert, J., Rao, S. B., Agholme, L., Brorsson, A.-C., Marcusson, J., Hallbeck, M. & Nath, S. (2014). Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance. Neurobiology of Disease, 65, 82-92
Open this publication in new window or tab >>Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance
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2014 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, p. 82-92Article in journal (Refereed) Published
Abstract [en]

The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Alzheimer's disease, Amyloid-β oligomers, Cell-to-cell transfer, Intracellular accumulation, Prion-like propagation
National Category
Cell Biology
Identifiers
urn:nbn:se:liu:diva-103179 (URN)10.1016/j.nbd.2013.12.019 (DOI)000333546300008 ()24412310 (PubMedID)
Available from: 2014-01-14 Created: 2014-01-14 Last updated: 2019-10-14Bibliographically approved
Hallbeck, M., Nath, S. & Marcusson, J. (2013). Neuron-to-Neuron Transmission of Neurodegenerative Pathology. The Neuroscientist, 19(6), 560-566
Open this publication in new window or tab >>Neuron-to-Neuron Transmission of Neurodegenerative Pathology
2013 (English)In: The Neuroscientist, ISSN 1073-8584, E-ISSN 1089-4098, Vol. 19, no 6, p. 560-566Article, review/survey (Refereed) Published
Abstract [en]

One of the hallmarks of neurodegenerative dementia diseases is the progressive loss of mental functions and the ability to manage activities of daily life. This progression is caused by the spread of the disease to more and more brain areas via anatomical connections. The pathophysiological process responsible for this spread of disease has long been sought after. There has been an increased understanding that the driving force of these neurodegenerative diseases could be the small, soluble intraneuronal accumulations of neurodegenerative proteins rather than the large, extracellular accumulations. Recently we have shown that the mechanism of spread of Alzheimer's disease most likely depends on the neuron-to-neuron spread of such soluble intraneuronal accumulations of -amyloid through neuritic connections. Similar transmissions have been shown for several other neurodegenerative proteins but little is known about the cellular mechanisms and about any potential strategies that might stop this spread. Resolving these questions requires good cellular models. We have established a unique model of synaptic transmission between human neuronal-like cells, something that has previously been difficult to target. This opens the possibility of developing potential inhibitors of progression of these devastating diseases.

Place, publisher, year, edition, pages
Sage Publications, 2013
Keywords
Alzheimer’s disease, neurodegeneration, β-amyloid, transmission, prion, cellular models
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-95927 (URN)10.1177/1073858413494270 (DOI)000326653000007 ()
Available from: 2013-08-11 Created: 2013-08-11 Last updated: 2019-10-14
Nath, S., Agholme, L., Roshan, F., Granseth, B., Marcusson, J. & Hallbeck, M. (2012). Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid. Journal of Neuroscience, 32(26), 8767-8777
Open this publication in new window or tab >>Spreading of Neurodegenerative Pathology via Neuron-to-Neuron Transmission of beta-Amyloid
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2012 (English)In: Journal of Neuroscience, ISSN 0270-6474, E-ISSN 1529-2401, Vol. 32, no 26, p. 8767-8777Article in journal (Refereed) Published
Abstract [en]

Alzheimers disease (AD) is the major cause of dementia. During the development of AD, neurofibrillary tangles progress in a fixed pattern, starting in the transentorhinal cortex followed by the hippocampus and cortical areas. In contrast, the deposition of beta-amyloid (A beta) plaques, which are the other histological hallmark of AD, does not follow the same strict spatiotemporal pattern, and it correlates poorly with cognitive decline. Instead, soluble A beta oligomers have received increasing attention as probable inducers of pathogenesis. In this study, we use microinjections into electrophysiologically defined primary hippocampal rat neurons to demonstrate the direct neuron-to-neuron transfer of soluble oligomeric A beta. Additional studies conducted in a human donor-acceptor cell model show that this A beta transfer depends on direct cellular connections. As the transferred oligomers accumulate, acceptor cells gradually show beading of tubulin, a sign of neurite damage, and gradual endosomal leakage, a sign of cytotoxicity. These observations support that intracellular A beta oligomers play a role in neurodegeneration, and they explain the manner in which A beta can drive disease progression, even if the extracellular plaque load is poorly correlated with the degree of cognitive decline. Understanding this phenomenon sheds light on the pathophysiological mechanism of AD progression. Additional elucidation will help uncover the detailed mechanisms responsible for the manner in which AD progresses via anatomical connections and will facilitate the development of new strategies for stopping the progression of this incapacitating disease.

Place, publisher, year, edition, pages
SOC NEUROSCIENCE, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-79695 (URN)10.1523/JNEUROSCI.0615-12.2012 (DOI)000305890700003 ()
Available from: 2012-08-13 Created: 2012-08-13 Last updated: 2019-10-14
Helmfors, L., Armstrong, A., Civitelli, L., Sandin, L., Nath, S., Janefjord, C., . . . Kågedal, K.A protective role of lysozyme in Alzheimer disease.
Open this publication in new window or tab >>A protective role of lysozyme in Alzheimer disease
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Alzheimer disease (AD) is a devastating neurodegenerative disorder where extracellular plaques composed of amyloid β (Aβ) peptides and neuroinflammation are some of the main hallmarks of the disease. Activated microglial cells, which are the resident macrophages in the central nervous system, are suggested to trigger the inflammation response in AD. To discover neuroinflammation biomarkers would be important to reveal the pathological mechanisms of AD and develop therapies that target inflammation mediators. Lysozyme is part of the innate immune system and is secreted from macrophages during various inflammation conditions. However, the involvement of lysozyme in AD pathology has not been explored previously. We have discovered that lysozyme is up-regulated in cerebrospinal fluid from AD patients. Cells exposed to Aβ increased the expression of lysozyme indicating that Aβ might be responsible for the upregulation of lysozyme detected in cerebrospinal fluid. In vitro studies revealed that lysozyme binds to monomeric Aβ1-42 and alters the aggregation pathway counteracting formation of toxic Aβ species. In a newly developed Drosophila model, co-expression of lysozyme with Aβ in brain neurons reduced the formation of insoluble Aβ species, prolonged the survival and improved the activity of the double transgenic flies compared to flies only expressing Aβ. Our findings identify lysozyme as a modulator of Aβ aggregation and toxicity and our discoveries has the potential to be used for development of new treatment strategies and to use lysozyme as a biomarker for AD.

Keywords
Lysozyme, Biomarker, Alzheimer disease, Drosophila, CSF, Aβ aggregation
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-106646 (URN)
Available from: 2014-05-16 Created: 2014-05-16 Last updated: 2014-05-16Bibliographically approved
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