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000162710 037__ $$aDZNE-2021-01367
000162710 041__ $$aEnglish
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000162710 1001_ $$0P:(DE-2719)2812097$$aBarth, Melanie$$b0$$eFirst author$$udzne
000162710 245__ $$aMicroglial inclusions and neurofilament light chain release follow neuronal α-synuclein lesions in long-term brain slice cultures.
000162710 260__ $$aLondon$$bBiomed Central$$c2021
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000162710 520__ $$aProteopathic brain lesions are a hallmark of many age-related neurodegenerative diseases including synucleinopathies and develop at least a decade before the onset of clinical symptoms. Thus, understanding of the initiation and propagation of such lesions is key for developing therapeutics to delay or halt disease progression.Alpha-synuclein (αS) inclusions were induced in long-term murine and human slice cultures by seeded aggregation. An αS seed-recognizing human antibody was tested for blocking seeding and/or spreading of the αS lesions. Release of neurofilament light chain (NfL) into the culture medium was assessed.To study initial stages of α-synucleinopathies, we induced αS inclusions in murine hippocampal slice cultures by seeded aggregation. Induction of αS inclusions in neurons was apparent as early as 1week post-seeding, followed by the occurrence of microglial inclusions in vicinity of the neuronal lesions at 2-3 weeks. The amount of αS inclusions was dependent on the type of αS seed and on the culture's genetic background (wildtype vs A53T-αS genotype). Formation of αS inclusions could be monitored by neurofilament light chain protein release into the culture medium, a fluid biomarker of neurodegeneration commonly used in clinical settings. Local microinjection of αS seeds resulted in spreading of αS inclusions to neuronally connected hippocampal subregions, and seeding and spreading could be inhibited by an αS seed-recognizing human antibody. We then applied parameters of the murine cultures to surgical resection-derived adult human long-term neocortical slice cultures from 22 to 61-year-old donors. Similarly, in these human slice cultures, proof-of-principle induction of αS lesions was achieved at 1week post-seeding in combination with viral A53T-αS expressions.The successful translation of these brain cultures from mouse to human with the first reported induction of human αS lesions in a true adult human brain environment underlines the potential of this model to study proteopathic lesions in intact mouse and now even aged human brain environments.
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000162710 650_7 $$2Other$$aAlpha-synuclein
000162710 650_7 $$2Other$$aMicroglia
000162710 650_7 $$2Other$$aNeurofilament light chain
000162710 650_7 $$2Other$$aSlice culture
000162710 650_2 $$2MeSH$$aAnimals
000162710 650_2 $$2MeSH$$aHumans
000162710 650_2 $$2MeSH$$aInclusion Bodies: pathology
000162710 650_2 $$2MeSH$$aMice
000162710 650_2 $$2MeSH$$aMicroglia: metabolism
000162710 650_2 $$2MeSH$$aMicroglia: pathology
000162710 650_2 $$2MeSH$$aNeurofilament Proteins: metabolism
000162710 650_2 $$2MeSH$$aNeurons: metabolism
000162710 650_2 $$2MeSH$$aNeurons: pathology
000162710 650_2 $$2MeSH$$aOrgan Culture Techniques: methods
000162710 650_2 $$2MeSH$$aSynucleinopathies
000162710 650_2 $$2MeSH$$aalpha-Synuclein: toxicity
000162710 7001_ $$0P:(DE-2719)2810940$$aBacioglu, Mehtap$$b1$$udzne
000162710 7001_ $$aSchwarz, Niklas$$b2
000162710 7001_ $$0P:(DE-2719)9000235$$aNovotny, Renata$$b3$$udzne
000162710 7001_ $$aBrandes, Janine$$b4
000162710 7001_ $$0P:(DE-2719)9000948$$aWelzer, Marc$$b5$$udzne
000162710 7001_ $$0P:(DE-2719)2812690$$aMazzitelli, Sonia$$b6$$udzne
000162710 7001_ $$0P:(DE-2719)2811581$$aHäsler, Lisa$$b7$$udzne
000162710 7001_ $$0P:(DE-2719)9000294$$aSchweighauser, Manuel$$b8$$udzne
000162710 7001_ $$aWuttke, Thomas V$$b9
000162710 7001_ $$0P:(DE-2719)9001451$$aKronenberg-Versteeg, Deborah$$b10$$udzne
000162710 7001_ $$aFog, Karina$$b11
000162710 7001_ $$aAmbjørn, Malene$$b12
000162710 7001_ $$aAlik, Ania$$b13
000162710 7001_ $$aMelki, Ronald$$b14
000162710 7001_ $$0P:(DE-2719)2810803$$aKahle, Philipp$$b15$$udzne
000162710 7001_ $$aShimshek, Derya R$$b16
000162710 7001_ $$aKoch, Henner$$b17
000162710 7001_ $$0P:(DE-2719)2000010$$aJucker, Mathias$$b18$$udzne
000162710 7001_ $$0P:(DE-2719)2812508$$aTanriöver, Gaye$$b19$$eLast author$$udzne
000162710 773__ $$0PERI:(DE-600)2244557-2$$a10.1186/s13024-021-00471-2$$gVol. 16, no. 1, p. 54$$n1$$p54$$tMolecular neurodegeneration$$v16$$x1750-1326$$y2021
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