The role of glial cells in alpha-synuclein pathology : Focus on degradation, cell-to-cell propagation and inflammation

• Growing evidence emphasizes the role of astrocytes and microglia in Parkinson’s disease (PD) and Alzheimer’s disease (AD). Yet, little is known about their impact on specific disease processes and if their involvement is beneficial or detrimental. The aim of this thesis was to further investigate the role of astrocytes and microglia in PD and AD. To this purpose, cultured human astrocytes and microglia were exposed to aggregates of alpha-synuclein (αSYN) or amyloid-beta (Aβ), proteins that are central to PD and AD brain pathology, respectively.In Paper I, the toxicity and cell-to-cell spreading of aggregated αSYN in human astrocytes were evaluated. We found that astrocytes can engulf large amounts of αSYN aggregates, which are stored inside the cells instead of being degraded. This intracellular storage was found to result in severe cellular stress. As a response, stressed astrocytes were shown to transfer αSYN via tunneling nanotubes (TNT) to healthy astrocytes.T cells have been observed to enter the PD brain, but little is known about which stationary cell types they interact with. In Paper II, the ability of astrocytes and microglia to act as antigen presenting cells in the presence of aggregated αSYN was investigated. Both astrocytes and microglia were capable of expressing major histocompatibility class I (MHCI) and MHCII. However, only astrocytes had the capacity to express other molecules crucial for T-cell activation, such as CD80 and CD86. MHCII expressing astrocytes were also found in close vicinity to T cells in the PD brain.In paper III, the cross-talk between microglia and astrocytes in the presence of αSYN and Aβ aggregates was examined. When cultured separately, microglia appeared to degrade αSYN and Aβ better than astrocytes. However, co-culture experiments showed that microglia and astrocytes have a synergistic effect on the clearance of protein aggregates. Cell-to-cell contact was revealed as one of the possible mechanisms by which astrocytes and microglia communicate with each other.In Paper IV, the molecular mechanisms by which the compound KYP-2407 enhances αSYN clearance was investigated. We found that KYP-2407 stimulates the auto-lysosomal pathway in the presence of αSYN aggregates. Calpain proteins, which increase αSYN aggregation and diminish autophagy in PD, were also shown to be reduced in the presence of KYP-2407.Taken together, this thesis contributes with novel and important knowledge to the potential role of astrocytes and microglia in PD and AD.

Nyckelord

Parkinson’s disease

alpha-synuclein

amyloid-beta

astrocytes

microglia

tunneling nanotubes

antigen presentation

T cells

glial crosstalk

degradation

KYP-2407

Medicinsk vetenskap

Medical Science

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