Astrocyte-secreted chaperones as a non-cell autonomous form of neuronal protection in Alzheimer's disease

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Currently, more than 46 million people worldwide and 850,000 people in the UK are living with dementia and Alzheimer's disease, a number that is expected to double every 20 years. Despite many efforts to find new disease-modifying therapies for this disease, recent clinical trials have failed to show significant benefits and currently patients are only treated with drugs that alleviate disease symptoms. Traditionally, drug discovery strategies have focused on neurons as the main targets in Alzheimer's and other brain disorders. In the brain, neurons are responsible for processing information, learning and memory, while other specialized brain cells called glial cells are necessary to maintain neuron health and to aid neuron function. To be able to design effective therapeutic strategies for Alzheimer's disease, we need to investigate not only how neurons become dysfunctional but also to better understand what is the contribution of glial cells to the degeneration of neurons and the disease progression. The aim of this project is to investigate how astrocytes, the most abundant type of glial cell, can protect neurons in Alzheimer's disease. If we are able to identify which are the factors released from astrocytes that mediate neuroprotection, we will be able to design effective therapeutic tools.This research program will be carried out at the Maurice Wohl Clinical Neuroscience Institute, a newly built highly interdisciplinary neuroscience center at King's College London. We have established complementary collaborations that will enable us to employ a number of models of Alzheimer's disease, including mouse neuron and glia cell cultures, mouse brain slices and human neurons derived from induced pluripotent stem cells from patients. Using these models, we will investigate what are the factors released from astrocytes that affect the accumulation of abnormal proteins in brain and we will determine how these factors can protect Alzheimer's disease neurons from dying. Our findings will provide pre-clinical evidence to support follow up therapeutic studies.This proposal will explore the potential benefits of increasing astrocyte-released factors as a potential therapeutic strategy to prevent loss of neuron function in Alzheimer's disease. This is a novel avenue of research, which could have a significant impact on our understanding of neurodegenerative mechanisms and that may identify new ways to treat Alzheimer's disease.