The role of astrocytes in Alzheimer’s and Parkinson’s disease

Decades of research have focused on neuronal abnormalities in Alzheimer's disease (AD) and Parkinson's disease (PD), while glial cells have been given much less attention. Astrocytes, the most common type of glial cell, have significant impact on overall brain health. The aim of our research is to understand how astrocytes contribute to the propagation of AD and PD. With this new approach, we hope to pave the way for novel treatment strategies.

Astrocytes images from our studies.

Changes in the AD and PD brain

In AD and PD, there is an accumulation of harmful proteins in the brain. Amyloid-beta and tau form large deposits in the AD brain, while aggregates of alpha-synuclein accumulate in the PD brain. Moreover, chronic inflammation increases during the course of the disease. Despite the fact that these pathological changes were described already a century ago, many questions remain regarding the underlying cellular mechanisms and how the disease propagates to other regions of the brain.

Astrocytes spread pathological protein aggregates

Our research demonstrate that astrocytes ingest and process, but fail to fully degrade aggregated amyloid-beta, tau, and alpha-synuclein. Instead, the protein aggregates are stored as large deposits in the astrocytes, which causes inflammation and cellular dysfunction. Importantly, we have shown that stressed astrocytes spread pathogenic protein aggregates to nearby cells via different routes. For example, astrocytes contact their neighbors with thin thread-like projections (nanotubes) and release vesicles containing partially degraded material, which cause damage to surrounding neurons. Taken together, our results indicate that astrocytes could be a potential treatment target for AD and PD.

Methods

To investigate how astrocytes affect various pathological processes, we have developed useful 2D and 3D disease models, based on human iPSC-derived astrocytes, neurons, and microglia. Using a battery of techniques, including live cell imaging, flow cytometry and immunostainings, as well as protein and lipid analyses, we are uncovering astrocyte-mediated disease mechanisms.

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