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Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The pre-symptomatic stage of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) occurs several decades before the clinical onset. Changes in the lysosomal network, i.e. the autophagosomal, endosomal and lysosomal vesicular system, are among the first alterations observed. There are currently no treatments to slow or cure neurodegenerative diseases, and there is a great need for discovery of treatment targets in cellular pathways where pathology pre-dates the neuronal death. It is also crucial to be able to diagnose neurodegenerative diseases earlier, both to enable early intervention treatment and aid in selecting clinical trial populations before the patient has widespread pathology.

This thesis aims at investigating the potential of lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease.

A targeted search for lysosomal network proteins was performed in cerebrospinal fluid (CSF) from AD patients, and seven proteins: early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), lysozyme, microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were elevated. The levels of EEA1, LAMP-1, LAMP-2, LC3, lysozyme and Rab3 were also measured in CSF from parkinsonian syndrome patients: PD, clinically diagnosed 4-repeat tauopathy, pathologically confirmed corticobasal degeneration (CBD) and pathologically confirmed progressive supranuclear palsy (PSP) patients. LAMP-1 and LAMP-2 were decreased in PD. LC3 and lysozyme levels were increased in 4-repeat tauopathy patients. EEA1 was decreased and lysozyme increased in PSP, and LAMP-1, LAMP-2, LC3 and lysozyme were increased in CBD. The lysosomal network proteins had different CSF protein profiles in all the parkinsonian syndromes, as well as in AD. It should be emphasized that only a select few of the lysosomal network proteins were observed to be changed, rather than a general change in lysosomal network proteins, which implicates the involvement of these seven proteins in specific pathological processes. The most interesting candidates, LAMP-2 and lysozyme, were selected for further study for their involvement in the pathology of AD.

Lysozyme was found to co-localise with Aβ plaques in AD patients and overexpression prolonged survival and improved the activity in a Drosophila model of AD. Lysozyme was found to alter the aggregation pathway of Aβ1-42, to counteract the formation of toxic Aβ species and to protect from Aβ1-42 induced cell toxicity. Aβ1-42 in turn was found to increase the expression of lysozyme in both neuronal and glial cells. These data suggest that lysozyme levels rise in AD as a compensatory response which is protective against Aβ associated toxicity.

LAMP-2 mRNA and protein were found increased in brain areas relevant for AD pathology and various cellular models showed complex involvement of LAMP-2 in Aβ related pathology, with extensive crosstalk between LAMP-2 and Aβ. Exposure to oligomeric Aβ1-42 caused an upregulation of LAMP-2 and in turn, overexpression of LAMP-2 caused a reduction in secreted levels of Aβ1-42, as well as changing the generation pattern of Aβ and affecting clearance and secretion of Aβ1-42. These data indicate that the increased levels of LAMP-2 in AD could be an attempt to regulate Aβ generation and secretion.

In summary, this thesis reports that utilising lysosomal network proteins as biomarkers and novel therapeutic targets for neurodegenerative diseases holds great promise.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 58 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1492
Keyword [en]
Cerebrospinal fluid (CSF), biomarkers, therapeutic targets, neurodegeneration, Alzheimer’s disease (AD), Parkinson’s disease (PD), Corticobasal degeneration (CBD), Progressive supraneuclear palsy (PSP), Lysosomes, Endosomes, Autophagy, LAMP-2, Lysozyme
National Category
Neurosciences Neurology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-122347DOI: 10.3384/diss.diva-122347ISBN: 978-91-7685-897-4 (print)OAI: oai:DiVA.org:liu-122347DiVA: diva2:865709
Public defence
2015-11-26, Eken, Campus US, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2015-10-30Bibliographically approved
List of papers
1. Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
Open this publication in new window or tab >>Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
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2014 (English)In: Neuromolecular medicine, ISSN 1535-1084, E-ISSN 1559-1174, Vol. 16, no 1, 150-160 p.Article in journal (Refereed) Published
Abstract [en]

The success of future intervention strategies for Alzheimers disease (AD) will likely rely on the development of treatments starting early in the disease course, before irreversible brain damage occurs. The pre-symptomatic stage of AD occurs at least one decade before the clinical onset, highlighting the need for validated biomarkers that reflect this early period. Reliable biomarkers for AD are also needed in research and clinics for diagnosis, patient stratification, clinical trials, monitoring of disease progression and the development of new treatments. Changes in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are among the first alterations observed in an AD brain. In this study, we performed a targeted search for lysosomal network proteins in human cerebrospinal fluid (CSF). Thirty-four proteins were investigated, and six of them, early endosomal antigen 1 (EEA1), lysosomal-associated membrane proteins 1 and 2 (LAMP-1, LAMP-2), microtubule-associated protein 1 light chain 3 (LC3), Rab3 and Rab7, were significantly increased in the CSF from AD patients compared with neurological controls. These results were confirmed in a validation cohort of CSF samples, and patients with no neurochemical evidence of AD, apart from increased total-tau, were found to have EEA1 levels corresponding to the increased total-tau levels. These findings indicate that increased levels of LAMP-1, LAMP-2, LC3, Rab3 and Rab7 in the CSF might be specific for AD, and increased EEA1 levels may be a sign of general neurodegeneration. These six lysosomal network proteins are potential AD biomarkers and may be used to investigate lysosomal involvement in AD pathogenesis.

Place, publisher, year, edition, pages
Humana Press, 2014
Keyword
PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-105235 (URN)10.1007/s12017-013-8269-3 (DOI)000331101900015 ()
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05
2. Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease
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, 122-133 p.Article 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
Keyword
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: 2017-12-01Bibliographically approved
3. Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
Open this publication in new window or tab >>Distinct lysosomal network protein profiles in parkinsonian syndrome cerebrospinal fluid
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2016 (English)In: Journal of Parkinson's Disease, ISSN 1877-7171, E-ISSN 1877-718X, Vol. 6, no 2, 307-315 p.Article in journal (Refereed) Published
Abstract [en]

Introduction: Clinical diagnosis of parkinsonian syndromes like Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy is hampered by overlapping symptomatology and lack of biomarkers for diagnosis, and definitive diagnosis is only possible post-mortem. Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that levels and profiles of lysosomal network proteins in cerebrospinal fluid could be changed in these parkinsonian syndromes.

Methods: Cerebrospinal fluid samples were collected from Parkinson’s disease patients (n=18), clinically diagnosed 4-repeat tauopathy patients, corticobasal syndrome (n=6) and progressive supranuclear palsy (n=5), pathologically diagnosed progressive supranuclear palsy (n=8) and corticobasal degeneration patients (n=7). Each patient set was compared to its appropriate control group consisting of the same number of age and gender matched individuals. Lysosomal network protein levels were detected via Western blotting.

Results: Lysosomal network proteins have markedly different cerebrospinal fluid protein levels and profiles in Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy. Lysosomal-associated membrane proteins 1 and 2 were significantly decreased in Parkinson´s disease; early endosomal antigen 1 was decreased and lysozyme increased in progressive supranuclear palsy; and lysosomal-associated membrane proteins 1 and 2, microtubule-associated protein 1 light chain 3 and lysozyme were increased in corticobasal degeneration.

Conclusions: Lysosomal network proteins hold promise of being interesting novel candidates for biomarker studies and for elucidating disease mechanisms of Parkinson’s disease, corticobasal degeneration and progressive supranuclear palsy, but further validation studies will be needed to assess the specificity and the predictive value of these proteins in CSF.

Place, publisher, year, edition, pages
IOS Press, 2016
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122342 (URN)10.3233/JPD-150759 (DOI)000378352200004 ()
Note

Funding agencies:This work was supported by the Swedish Alzheimer foundation, the Swedish Dementia foundation, Linkoping University Neurobiology Center, Karin & Sten CBD Solutions AB, AZ-KI TSC, ALF, US National Institutes of Health R01AG038791 and U54NS092089, the Tau Consortium, the Hellman Family Foundation.

Vid tiden för disputationen förelåg publikationen endast som manuskript

Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2017-05-02Bibliographically approved
4. The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
Open this publication in new window or tab >>The role of LAMP-2 in AβPP processing and Aβ degradation; implications for Alzheimer’s Disease
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2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Dysfunction in the lysosomal network, i.e., the endosomal, lysosomal and autophagy systems, are implicated in the pathways in Alzheimer’s disease brain pathology. This dysfunction is mirrored in the cerebrospinal fluid where a specific subset of lysosomal network proteins are found at elevated levels, lysosomal associated membrane protein-2 (LAMP-2) being one of the identified lysosomal proteins. Here we report that hippocampus and frontal cortex in Alzheimer’s disease cases have increased mRNA and protein expression of LAMP-2, and thus these brain areas are likely involved in the increased LAMP-2 levels seen in cerebrospinal fluid from Alzheimer’s disease patients. The increased LAMP-2 levels correlated with increased levels of β-amyloid1-42 (Aβ1-42). Oligomeric Aβ1-42 caused an upregulation of intracellular LAMP-2 in neuroblastoma cells, but did not trigger the release of LAMP-2 to the extracellular milieu, indicating that other cell types or mechanisms are responsible for the LAMP-2 release seen in cerebrospinal fluid. Overexpression of LAMP-2 in neuroblastoma cells caused a trend of reduction of secreted Aβ1-42 and changed the processing pattern of the Aβ precursor protein. These results indicate that Aβ1-42 mediated increase of LAMP-2 expression can act as a regulator of Aβ generation and secretion. LAMP-2 overexpression did not change the cellular uptake of extracellularly added Aβ1-42, but caused a delayed clearance of Aβ1-42. Whether the prolonged intracellular localization of Aβ1-42 in LAMP-2 overexpressing cells can change the transmission or degradation of Aβ remains to be investigated.

Keyword
AβPP processing, Alzheimer’s disease, β-amyloid, autophagy, LAMP-2, lysosome
National Category
Cell and Molecular Biology Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-122345 (URN)
Available from: 2015-10-29 Created: 2015-10-29 Last updated: 2015-10-29Bibliographically approved

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