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Lysosomal Network Proteins as Potential Novel CSF Biomarkers for Alzheimers Disease
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
Sahlgrens University Hospital, Sweden University of Calif San Francisco, CA 94143 USA .
Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
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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. Vol. 16, no 1, 150-160 p.
Keyword [en]
PICALM; DRAM; TFEB; Cathepsins; Proteasome; hsc70
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-105235DOI: 10.1007/s12017-013-8269-3ISI: 000331101900015OAI: oai:DiVA.org:liu-105235DiVA: diva2:705055
Available from: 2014-03-14 Created: 2014-03-14 Last updated: 2017-12-05
In thesis
1. Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
Open this publication in new window or tab >>Lysosomal network proteins as biomarkers and therapeutic targets in neurodegenerative disease
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
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:nbn:se:liu:diva-122347 (URN)10.3384/diss.diva-122347 (DOI)978-91-7685-897-4 (ISBN)
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

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