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APOEε2 drives tau processing and tau-mediated inflammation in human iPSC derived astrocytes
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- Mothes, Tobias (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Konstantinidis, Evangelos (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Eltom, Khalid (författare)
- Uppsala universitet,Institutionen för folkhälso- och vårdvetenskap
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- Engelska.
- Annan publikation (övrigt vetenskapligt/konstnärligt)
Abstract
Ämnesord
Stäng
- Background: Alzheimer’s disease (AD) and progressive supra-nuclear palsy (PSP) are both proteinopathies, characterized by accumulation of tau aggregates. APOEε4 is the greatest genetic risk factor for developing AD, while APOEε2 constitutes a decreased risk. On the contrary, APOEε2 is a significant risk factor for developing PSP. In the brain, astrocytes are the predominant producer of ApoE, but they are also important for synapse function, inflammation and overall brain homeostasis. Although, tau inclusions appear frequently in astrocytes in both AD and PSP brains, their connection to ApoE remains unclear. Methods: The aim of this study was to investigate how the APOEε-genotype influences astrocytes’ accumulation, processing and spreading of pathogenic tau aggregates, as well as their inflammatory status and neuronal support. For this purpose, we exposed isogenic hiPSC-derived APOE 2/2 and APOE 4/4 astrocytes to synthetic tau fibrils (Tau-F). Intracellular tau processing was analysed with immunocytochemistry and western blot, while secreted tau was analysed with ELISA. Cytokine levels in astrocyte conditioned medium (ACM) were measured with MesoScale analysis and seeding efficiency was examined using the Tau RD P301S FRET Biosensor and a close-culture chamber. Lastly, we exposed iPSC derived neurons to ACM from tau exposed astrocytes of both genotypes to assess potential neurotoxic effects.Results: Exposure to Tau-F resulted in more and larger intracellular tau-deposits in APOE 2/2 astrocytes, compared to APOE 4/4 astrocytes, while the tau levels in ACM remained similar. Western blot analysis demonstrated that the processing of internalized tau was clearly different between the genotypes. Moreover, APOE 2/2 was the dominant driver of inflammation with higher secreted levels of IL-8, CXCL10 and CCL2. The ApoE genotype did not influence neuronal health or direct seeding capacity of excreted tau. However, Tau-F had a 3-fold higher seeding efficiency when diluted in ACM from APOE 2/2 astrocytes, compared to APOE 4/4 astrocytes. Conclusions: Our results show that APOE 2/2 astrocytes accumulate, process and spread pathogenic tau aggregates more efficiently than APOE 4/4 astrocytes, highlighting a role of ApoE in astrocyte-mediated tau pathology. Moreover, the APOE 2/2 astrocytes display a more robust inflammatory response, which could be of relevance for the disease course.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- Alzheimer’s disease
- Progressive supra-nuclear palsy
- Astrocytes
- iPSC
- APOE
- Tau
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- Av författaren/redakt...
- Mothes, Tobias
- Konstantinidis, ...
- Eltom, Khalid
- Dakhel, Abdul
- Rostami, Jinar
- Erlandsson, Anna
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- MEDICIN OCH HÄLSOVETENSKAP
- MEDICIN OCH HÄLS ...
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- och Neurovetenskaper
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- Uppsala universitet
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