Thursday, April 18, 2024
4/18/2024
Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative dementia characterized by decline in memory and cognitive function. Currently there is no effective therapeutic intervention for AD. Synapse loss is one of the invariable pathological features and precedes AD symptom development. Considering that synapses function as fundamental units for information storage in the brain, synapse loss is highly likely to be responsible for the initial memory loss and cognitive decline in AD. Therefore, the prevention of synapse loss and/or restoration of synapse numbers may help improve memory and cognitive function of AD patients. The long term goal is to understand the molecular bases of synapse loss in AD to help develop new therapeutic strategies. Amyloid ¿ (A¿), a key molecule widely believed to underlie the pathophysiology of AD, is thought to be the main driver for the degeneration and loss of synapses and tau pathology. However, detailed molecular mechanisms by which A¿ elicits synapse loss are not fully understood. Wnt signaling plays an essential role in the formation and maintenance of synapses in the adult brain. Genetic and pathological evidence indicates that dysfunctional Wnt signaling is associated with AD and synapse loss. Proline-rich 7 (PRR7) is a newly identified Wnt inhibitor promoting the weakening and elimination of excitatory synapses. Aberrant expression of PRR7 is implicated in dementia and AD. However, no studies have been performed on the pathogenic role of PRR7 in dementia and AD. Remarkably, we found that central neurons secrete PRR7 to extracellular space via exosomes. PRR7-containing exosomes are subsequently absorbed by surrounding neurons and induces synapse loss in recipient neurons. Therefore, PRR7 has a potential ability to spread synapse loss in the brain under the conditions associated with AD. The central hypothesis of this project is that PRR7 is a critical mediator of the A¿-induced synapse degeneration in AD. This hypothesis has been formulated based on these findings and preliminary data showing that soluble oligomers of A¿¿induce the secretion of PRR7 on exosomes. In this project, the involvement of PRR7 in AD-associated synapse loss will be explored by using biochemical, cell biological, and genetic approaches. First, the requirement of PRR7 in A¿-induced excitatory synapses loss will be studied using cultured hippocampal neurons and an AD mouse model. Second, the role of PRR7-containing exosomes in the spread of synapse degeneration in local neurons will be investigated. The outcome of this research will advance our understanding of the pathogenic synapse loss mechanisms in AD and help design new therapeutic strategy for AD.
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