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Extracellular vesicles from amyloid-beta exposed cell cultures induce severe dysfunction in cortical neurons
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.ORCID-id: 0000-0002-5817-9547
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.ORCID-id: 0000-0001-5466-8370
Vise andre og tillknytning
2020 (engelsk)Inngår i: Scientific Reports, E-ISSN 2045-2322, Vol. 10, artikkel-id 19656Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Alzheimer's disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind the neurodegeneration is still unclear, but recent data suggests that spreading of amyloid-beta (A beta) pathology via extracellular vesicles (EVs) may contribute to disease progression. We have previously shown that an incomplete degradation of A beta (42) protofibrils by astrocytes results in the release of EVs containing neurotoxic A beta. Here, we describe the cellular mechanisms behind EV-associated neurotoxicity in detail. EVs were isolated from untreated and A beta (42) protofibril exposed neuroglial co-cultures, consisting mainly of astrocytes. The EVs were added to cortical neurons for 2 or 4 days and the neurodegenerative processes were followed with immunocytochemistry, time-lapse imaging and transmission electron microscopy (TEM). Addition of EVs from A beta (42) protofibril exposed co-cultures resulted in synaptic loss, severe mitochondrial impairment and apoptosis. TEM analysis demonstrated that the EVs induced axonal swelling and vacuolization of the neuronal cell bodies. Interestingly, EV exposed neurons also displayed pathological lamellar bodies of cholesterol deposits in lysosomal compartments. Taken together, our data show that the secretion of EVs from A beta exposed cells induces neuronal dysfunction in several ways, indicating a central role for EVs in the progression of A beta -induced pathology.

sted, utgiver, år, opplag, sider
NATURE RESEARCH , 2020. Vol. 10, artikkel-id 19656
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-428933DOI: 10.1038/s41598-020-72355-2ISI: 000595255700049PubMedID: 33184307OAI: oai:DiVA.org:uu-428933DiVA, id: diva2:1511592
Forskningsfinansiär
Swedish Research CouncilThe Swedish Brain FoundationGun och Bertil Stohnes StiftelseStiftelsen Gamla TjänarinnorTilgjengelig fra: 2020-12-18 Laget: 2020-12-18 Sist oppdatert: 2024-03-26bibliografisk kontrollert
Inngår i avhandling
1. Astrocytes in Alzheimer’s disease: Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
Åpne denne publikasjonen i ny fane eller vindu >>Astrocytes in Alzheimer’s disease: Exploring the impact of amyloid-β pathology on neurotoxicity, metabolism and inflammation.
2024 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Astrocytes play a central role in brain homeostasis, but are also tightly connected to the pathogenesis of Alzheimer’s disease (AD). Yet, their exact role in amyloid-beta (Aβ) pathology and chronic neuroinflammation is unclear. The aim of this thesis was to elucidate the impact of astrocytes in AD progression. For this purpose, astrocytes in different culture set-ups were exposed to soluble Aβ aggregates. The astrocytes engulf and process, but fail to fully degrade the Aβ aggregates, which are instead stored as large intracellular deposits. In Paper I, we show that extracellular vesicles (EVs), secreted from the Aβ-containing cells induce synaptic loss, axonal swelling and vacuolization of primary neurons, which consequently leads to apoptosis. 

Astrocytes play a central role in the brain’s energy metabolism and we were therefore interested in how Aβ pathology affects their metabolism. In Paper II, we report that Aβ accumulation in astrocytes disrupts mitochondrial fission/fusion homeostasis, resulting in decreased mitochondrial respiration and altered glycolysis. Interestingly, the astrocytes switch to fatty acid β oxidation with the aid of peroxisomes to maintain stable energy production. 

Another important task is to understand how astrocytes modify the ingested Aβ.  In Paper III, we characterized the astrocytic Aβ inclusions by isolating them with magnetic beads. Our analysis showed that the astrocytes truncate and pack together the Aβ aggregates. Moreover, we found that astrocytes release specifically truncated forms of Aβ via different routes.

Astrocytes’ involvement in lipid metabolism and inflammation has recently gained much interest, but many questions remain about the connection between these processes. In Paper IV, we show that Aβ pathology causes lipid droplet (LD) accumulation in astrocytes. Moreover, we could show that astrocytes frequently transfer LDs to neighboring cells, both through direct cell-to-cell contacts and via secretion. Astrocytes have previously been reported to express major histocompatibility complex II (MHCII) and have the capacity to perform as professional antigen presenting cells. Interestingly, our results demonstrate that LDs contain MHCII, identifying a link between LDs and inflammation in astrocytes.

Taken together, this thesis contributes with important knowledge of the role of astrocytes in AD pathology. 

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis, 2024. s. 66
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2041
Emneord
Alzheimer’s disease, astrocytes, amyloid-beta, extracellular vesicles, mitochondria, lipid droplets, lipid metabolism, inflammation
HSV kategori
Forskningsprogram
Molekylär medicin
Identifikatorer
urn:nbn:se:uu:diva-525110 (URN)978-91-513-2089-2 (ISBN)
Disputas
2024-05-17, Rudbecksalen, Rudbeck Laboratory, Dag Hammarskjölds Väg 20, Uppsala, 09:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2024-04-25 Laget: 2024-03-26 Sist oppdatert: 2024-04-25

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