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The Aβ protofibril selective antibody mAb158 prevents accumulation of Aβ in astrocytes and rescues neurons from Aβ-induced cell death.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular Geriatrics)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. (Molecular Geriatrics)
BioArctic Neuroscience AB.
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(English)In: Article in journal (Refereed) Submitted
Keyword [en]
Alzheimer’s disease, amyloid-β, antibody, clearance, astrocyte, neuron
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-264223OAI: oai:DiVA.org:uu-264223DiVA: diva2:861135
Available from: 2015-10-15 Created: 2015-10-07 Last updated: 2017-11-28
In thesis
1. Amyloid-β Protofibrils in Alzheimer´s Disease: Focus on Antibodies, Inflammation and Astrocytes
Open this publication in new window or tab >>Amyloid-β Protofibrils in Alzheimer´s Disease: Focus on Antibodies, Inflammation and Astrocytes
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Soluble amyloid-beta (Aβ) aggregates, including Aβ protofibrils, play a central role in Alzheimer’s disease (AD) and constitute a potential diagnostic biomarker and a therapeutic target. Aβ protofibrils promote synapse dysfunction and neurodegeneration, but the mechanisms behind these effects remain unclear. The aim of this thesis was to increase the knowledge of Aβ protofibrils in AD pathology.

When measuring low abundant antigens, such as soluble Aβ aggregates, in plasma and CSF by immunoassays, there is a possibility of interference by heterophilic antibodies (HA). In paper I, we show that HA generate false positive signals, by cross-binding the assay antibodies, when plasma and CSF from AD patients and healthy controls were analyzed for soluble Aβ aggregates, using sandwich ELISAs.

Natural anti-Aβ antibodies exist in AD patients and healthy individuals. Circulating Aβ and anti-Aβ antibodies may form immune complexes, masking epitopes on the anti-Aβ antibody, which makes the anti-Aβ antibody concentration difficult to measure. In paper II, the ELISpot technique enabled us to successfully measure B cell production of anti-Aβ antibodies. Our results show that anti-Aβ protofibril antibody production is present in both AD patients and healthy individuals, but is significantly higher in AD patients, indicating that the immune system attempt to eliminate the toxic Aβ species.

Insufficient lysosomal degradation is proposed to cause sporadic AD. In paper III, we used a co-culture system of astrocytes, neurons and oligodendrocytes, to clarify the role of astrocytes in Aβ protofibril clearance. Astrocytes are the most prominent glial cell type in the brain, but their role in AD remains elusive. We found that astrocytes effectively engulf, but inefficiently degrade Aβprotofibrils. This result in a high intracellular load of toxic, partly N-terminally truncated Aβ and lysosomal dysfunction. Moreover, we found that secretion of microvesicles, containing N-terminally truncated Aβ, induce neuronal apoptosis. In paper IV, we show that treatment with the protofibril selective antibody mAb158 lead to enhanced Aβ clearance and thereby prevent Aβ neurotoxicity.

Taken together, this thesis contributes with important knowledge on the role of Aβ protofibrils in AD pathogenesis and technical aspects that should be considered when measuring Aβ in human tissues.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 72 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1147
Keyword
Alzheimer's Disease, Amyloid-beta, Protofibrils, ELISA, ELISpot, Astrocyte, Monoclonal Antibody, Immunofluorescence
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-264647 (URN)978-91-554-9373-8 (ISBN)
Public defence
2015-12-04, Rudbecksalen, Rudbeckslaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2015-11-13 Created: 2015-10-15 Last updated: 2016-01-14Bibliographically approved
2. Cellular responses to amyloid-beta protofibrils: Focus on astrocytes, extracellular vesicles and antibody treatment
Open this publication in new window or tab >>Cellular responses to amyloid-beta protofibrils: Focus on astrocytes, extracellular vesicles and antibody treatment
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Knowledge about the cellular mechanisms behind the initiation and propagation of Alzheimer’s disease (AD) is limited. Decades of research have focused on neuronal abnormalities in AD, but recently more attention has been given to the glial cells. Being the most numerous glial cell type in the brain, astrocytes are important for many functions, but their role in AD is poorly understood. The aim with this thesis was to clarify the involvement of astrocytes in AD by using a co-culture system of primary neurons and glia. The co-cultures were exposed to soluble amyloid-beta (Aβ) aggregates, i.e. protofibrils that are known to be particularly harmful.

In Paper I, the capacity of astrocytes to ingest and degrade Aβ protofibrils was investigated. We found that astrocytes effectively ingested Aβ, but were ineffective in degrading the material. The intracellular accumulation of Aβ in astrocytes resulted in lysosomal dysfunction, high intracellular load of partly N-terminally truncated Aβ and extracellular vesicle (EV) mediated neuronal cell death.

Cells can communicate by releasing cargo into EVs, but the role of EVs in the spreading of Aβ pathology is unclear. In Paper II, the protein content of EVs released specifically following Aβ protofibril exposure was analyzed. We found markedly increased levels of apolipoprotein E (apoE) in EVs from Aβ protofibril exposed co-cultures, suggesting a role for intercellular transfer of apoE in Aβ pathology.

Passive immunotherapy has been suggested as a promising therapeutic strategy for AD. In Paper III, we investigated if the Aβ protofibril-selective antibody mAb158 could affect Aβ clearance in the co-culture. The mAb158 treatment reduced Aβ accumulation in astrocytes and rescued neurons from Aβ-induced cell death.

In Paper IV, we explored the effect of EVs, isolated from Aβ protofibril exposed co-cultures on cultured neurons. In addition to increased cell death, we found that such EVs had a strong negative impact on the synapses, dendrites and mitochondria of the neurons.

Taken together, this thesis contributes with important knowledge about the role of astrocytes in Aβ pathology, the vesicle-mediated spreading of Aβ and the effects of anti-Aβ antibody treatment.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1405
Keyword
Alzheimer’s disease, Amyloid-beta, Protofibrils, Astrocytes, Extracellular vesicles, Antibody, Neurons, Degradation
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-334358 (URN)978-91-513-0173-0 (ISBN)
Public defence
2018-02-09, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-01-17 Created: 2017-11-28 Last updated: 2018-01-17

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