Reduced retromer function results in the accumulation of amyloid-beta oligomers

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Ansell - Schultz, AnnaLinköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten (författare)

Reduced retromer function results in the accumulation of amyloid-beta oligomers

Artikel/kapitelEngelska2018

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Academic Press,2018
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LIBRIS-ID:oai:DiVA.org:liu-153828
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-153828URI
https://doi.org/10.1016/j.mcn.2018.09.003DOI

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Språk:engelska
Sammanfattning på:engelska

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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
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.

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Reyes, JuanLinköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten(Swepub:liu)juare50 (författare)
Samuelsson, MyLinköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten,Region Östergötland, Klinisk patologi(Swepub:liu)mysa35 (författare)
Hallbeck, MartinLinköpings universitet,Avdelning för neurobiologi,Medicinska fakulteten,Region Östergötland, Klinisk patologi(Swepub:liu)marha90 (författare)
Linköpings universitetAvdelning för neurobiologi (creator_code:org_t)

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Ingår i:Molecular and Cellular Neuroscience: Academic Press93, s. 18-261044-74311095-9327

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Av författaren/redakt...: Ansell - Schultz ...; Reyes, Juan; Samuelsson, My; Hallbeck, Martin

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MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Medicinska och f ...; och Cell och molekyl ...

Artiklar i publikationen: Molecular and Ce ...

Av lärosätet: Linköpings universitet

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