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Reduced retromer function results in the accumulation of amyloid-beta oligomers
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.ORCID-id: 0000-0001-6716-0314
2018 (Engelska)Ingår i: Molecular and Cellular Probes, ISSN 1044-7431, E-ISSN 1095-9327, Vol. 93, s. 18-26Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Alzheimers disease (AD) is a neurodegenerative disorder characterized by a progressive loss of multiple cognitive functions. Accumulation of amyloid beta oligomers (oA beta) play a major role in the neurotoxicity associated with the disease process. One of the early affected brain regions is the hippocampus, wherein a reduction of the vacuolar protein sorting-associated protein 35 (VPS35), the core protein comprising the retromer complex involved in cellular cargo sorting, has been identified. To investigate the role of the retromer function on the accumulation and clearance of oA beta, we reduced retromer function by selectively inhibiting VPS35 gene expression using siRNA in differentiated neuronal SH-SY5Y cells. As cell-to-cell transfer of oA beta to new brain regions is believed to be important for disease progression we investigated the effect of VPS35 reduction both in cells with direct uptake of oA beta and in cells receiving oA beta from donor cells. We demonstrate that reduced retromer function increases oA beta accumulation in both cell systems, both the number of cells containing intracellular oA beta and the amount within them. This effect was shown at different time points and regardless if the AD originated from the extracellular milieu or via a direct neuronal cell-to-cell transfer. Interestingly, not only did reduced VPS35 cause oA beta accumulation, but oA beta treatment alone also lead to a reduction of VPS35 protein content. The accumulated oA beta seems to co-localize with VPS35 and early endosome markers. Together, these findings provide evidence that reduced retromer function decreases the ability for neurons to transport and clear neurotoxic oA beta received through different routes resulting in the accumulation of oA beta. Thus, enhancing retromer function may be a potential therapeutic strategy to slow down the pathophysiology associated with the progression of AD.

Ort, förlag, år, upplaga, sidor
Academic Press, 2018. Vol. 93, s. 18-26
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:liu:diva-153828DOI: 10.1016/j.mcn.2018.09.003ISI: 000454470700003PubMedID: 30257187Scopus ID: 2-s2.0-85054185822OAI: oai:DiVA.org:liu-153828DiVA, id: diva2:1278043
Anmärkning

Funding Agencies|Swedish Research Council [MH: 523-2013-2735]; Swedish Alzheimer Foundation; Swedish Brain Foundation; Parkinson Research Foundation; Swedish Parkinson 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 Centre; County Council of Ostergotland

Tillgänglig från: 2019-01-11 Skapad: 2019-01-11 Senast uppdaterad: 2019-10-14Bibliografiskt granskad

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Ansell - Schultz, AnnaReyes, JuanSamuelsson, MyHallbeck, Martin
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Avdelning för neurobiologiMedicinska fakultetenKlinisk patologi
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