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The Propagation of Neurodegenerative Diseases by Inflammation and Exosomes
Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. (Hallbeck)ORCID iD: 0000-0002-6131-1764
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common neurodegenerative diseases with rates increasing along with the ageing global population. Despite best efforts, we still do not understand the etiopathogenesis of these diseases and there are no effective disease-modifying treatments. Cognitive deficiencies or motor complications that emerge during AD and PD are thought to be the result of the accumulation of misfolded, aggregate-prone proteins, such as amyloid-β (Aβ) and tau or α-synuclein (α-syn), respectively. Growing evidence suggests that prefibrillar oligomers of Aβ and α-syn (oAβ and oα-syn) are key contributors to the progression of these diseases. The progressive accumulation of these proteins leads to a gradual spread of pathology throughout interconnected brain regions, but the mechanisms by which this spreading occurs are still largely unknown.

Neuroinflammation has been recognised as an important contributor to neurodegenerative disease. It is hypothesised that a pro-inflammatory environment initiated by the innate immune system, either through activation from Aβ itself or indirectly through neuronal injury signals in AD. These phenomena are thought to either cause or accelerate AD, such that an anti-inflammatory approach may be neuroprotective. In paper I, we investigated whether different inflammatory environments affected the transfer of oAβ between neuron-like cells, in addition to investigating inter- and intracellular protein changes. This study demonstrated that an anti-inflammatory environment reduces the transfer of oAβ between cells. We also provide evidence that these cells begin to take on the “phenotype” of the inflammatory milieu, while also demonstrating that the expression profile of endosomal/lysosomal and protein trafficking proteins is altered during these conditions.

Small extracellular vesicles called exosomes, which are key players in cell to cell communication, have been proposed to play an influential role in spreading neurodegenerative proteins between cells. Exosomes are small membranous vesicles that are formed by the inward budding of multivesicular bodies (MVBs). These MVBs can then merge with the plasma membrane to be released into the extracellular environment as vesicles, which serve as vehicles for transferring proteins, lipids, and mRNAs between cells.

The ESCRT-dependent pathway is the most understood mechanism underlying exosome biogenesis. However, exosomes can also be formed through ESCRT-independent pathways, including through the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2), which produces ceramide. Paper II investigated whether exosomes formed through an ESCRT-independent pathway plays a significant role in the transfer of oα-syn between neuron-like cells. As oxidative stress is a common feature in PD brains, which in turn dysregulates nSMase2 activity, we also tested our model under hypoxic conditions. Inhibition of nSMase2 significantly reduced the transfer of oα-syn between cells but also resulted in decreased α-syn aggregation. Hypoxia did not influence oα-syn transfer, however, it significantly dysregulated the sphingolipid composition, which may be important for α-syn binding to exosomes and exosome communication.

During AD and PD, there is a noted reduction in the effectiveness of autophagy, a process critical to cellular proteostasis. Recent studies have uncovered shared regulatory mechanisms of exosome biogenesis and autophagy, suggesting that they are closely linked. Previous findings have shown that inhibition of autophagy in AD mice mediates Aβ trafficking through altering the secretion of Aβ in MVBs. To further study this effect, we investigated the interplay between autophagy and exosome secretion using ATG7 knock-out x APPNL-F knock-in AD mice in paper III. These autophagy-deficient AD mice had a reduced extracellular Aβ plaque load, but increased intracellular Aβ, which was found to be assembled into higher-ordered assemblies. While exosomal secretion was dysregulated in these mice, the amount of Aβ packaged into the exosomes was unchanged.

Lastly, one of the biggest challenges in developing effective treatments for AD is the lack of early diagnosis of living patients. As the connection between exosomes and the spread of neurodegenerative proteins is still relatively new, there remains a diagnostic potential to be explored with exosomes. Paper IV aimed to develop a new diagnostic assay to detect oAβ in exosomes isolated from human cerebrospinal fluid. Although exosomal oAβ was readily detected in some of these samples, the assay’s sensitivity requires additional optimisation before it can be further validated for the clinic.

In summary, the studies presented in this thesis have furthered our understanding of how inflammation, autophagy, and exosomes contribute to the intercellular transmission of AD and PD associated proteins. We have shown that an anti-inflammatory approach may slow down the progression of AD through reducing the transfer of oAβ between cells. We also provide novel findings relating to the biogenesis of exosomes, which in turn affected the ability of exosomes to transmit neurodegenerative proteins between cells, and their association with autophagic processes. Finally, we have investigated the feasibility of exosomes as an early AD diagnostic marker. This work has helped to elucidate some of the mechanisms underlying the progression of neurodegenerative diseases, which may be useful targets for the investigation of new therapeutic avenues.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. , p. 60
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1703
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:liu:diva-160949DOI: 10.3384/diss.diva-160949ISBN: 9789175190129 (print)OAI: oai:DiVA.org:liu-160949DiVA, id: diva2:1361528
Public defence
2019-11-21, Berzeliussalen, Building 463, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-11-05Bibliographically approved
List of papers
1. Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells
Open this publication in new window or tab >>Anti-inflammatory (M2) macrophage media reduce transmission of oligomeric amyloid beta in differentiated SH-SY5Y cells
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2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 60, p. 173-182Article in journal (Refereed) Published
Abstract [en]

Neuroinflammation plays an influential role in Alzheimers disease (AD), although the mechanisms underlying this phenomenon remain largely unknown. Microglia are thought to be responsible for the majority of these effects and can be characterized into resting (M0), proinflammatory (M1), or anti-inflammatory (M2) functional phenotypes. We investigated the effects of conditioned macrophage media, as an analogue to microglia, on the transfer of oligomeric amyloid beta (oA beta) between differentiated SH-SY5Y cells. We also investigated how the different inflammatory environments related to intercellular and intracellular changes. We demonstrate that M2 products decrease interneuronal transfer of oA beta, while recombinant interleukin (IL)-4, IL-10, and IL-13 increase transfer. There were no alterations to the mRNA of a number of AD-related genes in response to the combination of oA beta and M0, M1, or M2, but several intracellular proteins, some relating to protein trafficking and the endosomal/lysosomal system, were altered. Stimulating microglia to an M2 phenotype may thus slow down the progression of AD and could be a target for future therapies. (C) 2017 Elsevier Inc. All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE INC, 2017
Keywords
Anti-inflammatory; Proinflammatory; Amyloid beta oligomers; Cytokine; Cell-to-cell transfer; Alzheimers disease
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-143067 (URN)10.1016/j.neurobiolaging.2017.08.022 (DOI)000414424800016 ()28969867 (PubMedID)
Note

Funding Agencies|Swedish Research Council [523-2013-2735]; Swedish Alzheimer foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Gustav V and Queen Victorias Foundation; Swedish Dementia Foundation; Linkoping University Neurobiology Centre; County Council of Ostergotland

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2019-10-16
2. Inhibition of nSMase2 Reduces the Transfer of Oligomeric alpha-Synuclein Irrespective of Hypoxia
Open this publication in new window or tab >>Inhibition of nSMase2 Reduces the Transfer of Oligomeric alpha-Synuclein Irrespective of Hypoxia
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2019 (English)In: Frontiers in Molecular Neuroscience, ISSN 1662-5099, Vol. 12, article id 200Article in journal (Refereed) Published
Abstract [en]

Recently, extracellular vesicles (EVs), such as exosomes, have been proposed to play an influential role in the cell-to-cell spread of neurodegenerative diseases, including the intercellular transmission of alpha-synuclein (alpha-syn). However, the regulation of EV biogenesis and its relation to Parkinsons disease (PD) is only partially understood. The generation of EVs through the ESCRT-independent pathway depends on the hydrolysis of sphingomyelin by neutral sphingomyelinase 2 (nSMase2) to produce ceramide, which causes the membrane of endosomal multivesicular bodies to bud inward. nSMase2 is sensitive to oxidative stress, a common process in PD brains; however, little is known about the role of sphingomyelin metabolism in the pathogenesis of PD. This is the first study to show that inhibiting nSMase2 decreases the transfer of oligomeric aggregates of alpha-syn between neuron-like cells. Furthermore, it reduced the accumulation and aggregation of high-molecular-weight alpha-syn. Hypoxia, as a model of oxidative stress, reduced the levels of nSMase2, but not its enzymatic activity, and significantly altered the lipid composition of cells without affecting EV abundance or the transfer of alpha-syn. These data show that altering sphingolipids can mitigate the spread of alpha-syn, even under hypoxic conditions, potentially suppressing PD progression.

Place, publisher, year, edition, pages
FRONTIERS MEDIA SA, 2019
Keywords
Parkinsons disease; extracellular vesicles; neutral sphingomyelinase 2; alpha-syn; hypoxia; cell-to-cell transmission; sphingomyelin; ceramide
National Category
Neurosciences
Identifiers
urn:nbn:se:liu:diva-160421 (URN)10.3389/fnmol.2019.00200 (DOI)000482932300001 ()
Note

Funding Agencies|Swedish Research Council [523-2013-2735]; Swedish Brain Foundation; Research Foundation of the Swedish Parkinsons Disease Association; Ostergotland Research Foundation for Parkinsons Disease; Parkinson Research Foundation; Swedish Alzheimers Foundation; Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research; Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse; Swedish Dementia Foundation; Linkoping University Neurobiology Center; County Council of Ostergotland

Available from: 2019-09-23 Created: 2019-09-23 Last updated: 2019-11-28

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