Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition: Involvement of Autophagy

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Fältnamn	Indikatorer	Metadata
000		04177naa a2200457 4500
001		oai:DiVA.org:liu-81340
003		SwePub
008		120912s2012 \| \|\|\|\|\|\|\|\|\|\|\|000 \|\|eng\|
009		oai:prod.swepub.kib.ki.se:125092773
024	7	a https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-813402 URI
024	7	a https://doi.org/10.3233/JAD-2012-1200012 DOI
024	7	a http://kipublications.ki.se/Default.aspx?queryparsed=id:1250927732 URI
040		a (SwePub)liud (SwePub)ki
041		a engb eng
042		9 SwePub
072	7	a ref2 swepub-contenttype
072	7	a art2 swepub-publicationtype
100	1	a Agholme, Lottau Linköpings universitet,Geriatrik,Hälsouniversitetet4 aut0 (Swepub:liu)lothe38
245	1 0	a Amyloid-β Secretion, Generation, and Lysosomal Sequestration in Response to Proteasome Inhibition :b Involvement of Autophagy
264	1	b I O S Press,c 2012
338		a print2 rdacarrier
500		a funding agencies\|foundations of Engqvist, Wiberg, Hedlund, Osterman, and Stohne\|\|Gustav V and Queen Victorias Foundation\|\|Swedish Alzheimers foundation\|\|Ostergotland County Council\|\|Swedish Research Council\|\|
520		a The proteasome is important for degradation of worn out and misfolded proteins. Decreased proteasome activity has been implicated in Alzheimer's disease (AD). Proteasome inhibition induces autophagy, but it is still unknown whether autophagy is beneficial or deleterious to AD neurons, as the autophagosome has been suggested as a site of amyloid-β (Aβ) generation. In this study, we investigated the effect of proteasome inhibition on Aβ accumulation and secretion, as well as the processing of amyloid-β protein precursor (AβPP) in AβPPSwe transfected SH-SY5Y neuroblastoma cells. We show that proteasome inhibition resulted in autophagy-dependent accumulation of Aβ in lysosomes, and increased levels of intracellular and secreted Aβ. The enhanced levels of Aβ could not be explained by increased amounts of AβPP. Instead, reduced degradation of the C-terminal fragment of AβPP (C99) by the proteasome makes C99 available for γ-secretase cleavage, leading to Aβ generation. Inhibition of autophagy after proteasome inhibition led to reduced levels of intracellular, but not secreted Aβ, and tended to further increase the C99 to AβPP ratio, supporting involvement of the autophagosome in Aβ generation. Furthermore, proteasome inhibition caused a reduction in cellular viability, which was reverted by inhibition of autophagy. Dysfunction of the proteasome could cause lysosomal accumulation of Aβ, as well as increased generation and secretion of Aβ, which is partly facilitated by autophagy. As a decrease in cellular viability was also detected, it is possible that upregulation of autophagy is an unsuccessful rescue mechanism, which instead of being protective, contributes to AD pathogenesis.
653		a AβPP processing
653		a Alzheimer’s disease
653		a amyloid- peptide
653		a autophagy
653		a cell death
653		a LC-3
653		a lysosome
653		a p70S6K
653		a proteasome
700	1	a Hallbeck, Martinu Östergötlands Läns Landsting,Linköpings universitet,Experimentell patologi,Hälsouniversitetet,Klinisk patologi och klinisk genetik4 aut0 (Swepub:liu)marha90
700	1	a Benedikz, Eirikuru Karolinska Institutet,Department of Neurobiology, Division of Neurodegeneration, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden4 aut
700	1	a Marcusson, Janu Östergötlands Läns Landsting,Linköpings universitet,Geriatrik,Hälsouniversitetet,Geriatriska kliniken4 aut0 (Swepub:liu)janma25
700	1	a Kågedal, Katarinau Linköpings universitet,Experimentell patologi,Hälsouniversitetet4 aut0 (Swepub:liu)katka10
710	2	a Linköpings universitetb Geriatrik4 org
773	0	t Journal of Alzheimer's Diseased : I O S Pressg 31:2, s. 343-358q 31:2<343-358x 1387-2877x 1875-8908
856	4 8	u https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-81340
856	4 8	u https://doi.org/10.3233/JAD-2012-120001
856	4 8	u http://kipublications.ki.se/Default.aspx?queryparsed=id:125092773

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Av författaren/redakt...: Agholme, Lotta; Hallbeck, Martin; Benedikz, Eiriku ...; Marcusson, Jan; Kågedal, Katarin ...

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Av lärosätet: Linköpings universitet; Karolinska Institutet

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