Synapse Pruning by Astrocytes: A Potential New Target for Treating Alzheimer’s Disease

2017 and 2018

2018

How can we restore impaired brain homeostasis in Alzheimer’s disease (AD)? Previously, we have found that astrocytes, a star-shaped glial cell of the central nervous system, participates in clearing synaptic and neuronal debris in the brain. Through research funded by Cure Alzheimer’s Fund, we uncovered that astrocytes lose their capacity to clear out amyloid beta when they are pre-exposed to amyloid beta oligomers. These data suggest that one of the potential reasons for amyloid beta accumulation in AD is that the initial production of amyloid beta oligomers may change the gene expression patterns of astrocytes. This change in gene expression reduces their ability to uptake amyloid beta. By examining changes in mRNA expression of astrocytes with or without the pre-exposure to amyloid beta, we have found several critical candidate genes, including LDLR, which can be responsible for the reduced uptake by astrocytes. In the next funding period, we are aiming to test the following hypothesis: restoring astrocyte-mediated engulfment in the early AD brain reduces the accumulation of debris as well as amyloid beta burdens. We think our research will provide new therapeutic strategies in treating AD by correcting defective functions of astrocytes.

2017

There is profound synapse loss in the early stages of Alzheimer’s disease progression. However, it is unclear what triggers synapse loss and how we can prevent this process. Recently, we have found that astrocytes phagocytose and eliminate synapses in the developing and adult healthy brain, suggesting astrocytes may maintain synaptic/brain homeostasis by constantly cleaning up unnecessary synapses and synaptic debris. In this proposal, we will investigate whether the phagocytic capacity of astrocytes is impaired in the initiation and progression of Alzheimer’s disease, and whether we can develop new therapies to stimulate phagocytosis by astrocytes.


Funding to Date

$300,000

Focus

Foundational Genetics, Immune System Structures

Researchers

Won-Suk Chung, Ph.D.