P2Y6 Activation-mediated Clearance of Amyloid Plaque
Principal Investigator
Mentors
Project Goals
Microglia express the metabotropic P2Y6 receptor, whose activation by its endogenous agonist uridine diphosphate (UDP) triggers phagocytosis in response to neuronal injury. Given that the UDP/P2Y6 receptor system functions as a sensor of phagocytosis and initiates the clearance of debris in the brain, the main research objective of this study is to test the hypothesis that activation of the P2Y6 receptor results in amyloid plaque clearance and synaptic and cognitive improvement in an animal model of Alzheimer's disease (AD), and the PSAPP transgenic mouse.
Project Summary
Accumulation of amyloid beta within neuritic plaques is a defining feature of Alzheimer's disease (AD) and shows a strong correlation with the degree of neurological dysfunction. It has been suggested that microglial phagocytosis contributes to clearance of amyloid beta deposits. Recently, it has been shown that neurodegeneration stimulates microglial expression of the metabotropic P2Y6 receptor, whose activation by endogenous agonist uridine diphosphate (UDP) triggers microglial phagocytosis. The main research objective of this project is to examine whether the activation of the P2Y6 receptor in vivo reduces plaque burden in the brain, leads to recovery of amyloid-associated neuritic dystrophy, and improves behavioral performance in the mice model of AD. These aims will be addressed using a transgenic animal model of AD, the PSAPP transgenic mice, in combination with two-photon in vivo imaging, immunohistochemistry, electrophysiological and behavioral assays. In the first aim, the hypothesis that activation of P2Y6 induces clearance of plaque will be tested using acute administration of P2Y6 endogenous agonist, UDP, in the brain of PSAPP mice, followed by plaque evaluation using two-photon in vivo imaging and immunohistochemistry. The second aim is to determine whether activation of P2Y6 rescues deficits in synaptic plasticity and transmission in PSAPP mice using the electrophysiological method. In the third aim I will employ cognitive behavior tasks, including a fear conditioning test and novel object recognition, to test whether P2Y6-mediated plaque clearance improves cognitive capability in PSAPP mice. Currently, AD afflicts approximately 30 million people worldwide and is the most common cause of dementia in the elderly and there is no cure for the disease. Given the central role of amyloid beta peptide in the neuropathology of AD, efficient clearance of amyloid beta plaque becomes the focus of many therapeutic approaches in AD. These studies are designed to examine the role P2Y6 receptor in reduction of plaque burden in the brain, and have the potential to provide new therapeutic strategies for treatment of AD.
Progress Updates
Accumulation of beta-amyloid peptide is a defining feature of AD and shows a strong correlation with the degree of neurological dysfunction. It has been suggested that microglial phagocytosis (the process of “swallowing” and destroying virus, bacteria and other foreign or toxic objects) of beta-amyloid deposits is a major clearance pathway in AD pathology. Activation of the P2Y6 receptor protein has been shown to mediate microglial phagocytosis in response to brain injury.
In this study, Dr. Dong’s team found that activation of P2Y6 receptor stimulated the clearance of amyloid plaque in a mouse model of AD (called PS1/APP). This activity was assessed by labeling and imaging of proteins in a live mouse (with a technique called longitudinal two-photon in vivo imaging), and by detecting soluble Abeta protein in brain tissue (with techniques called immunostaining and ELISA). Activation of P2Y6 receptor significantly increased uptake of amyloid peptide by CD11-positive microglial cells, as analyzed using a cell-sorting technique, called flow cytometry. This suggests that P2Y6 receptor-mediated microglial phagocytosis contributes to Abeta clearance. Activation of P2Y6 also restored synaptic plasticity (nerve cell contact points for communication) and reversed hippocampal-dependent contextual memory in PS1/APP mice. Taken together, Dr. Dong’s team has uncovered data that suggests the activation of microglial P2Y6 receptors leads to a reduction in plaque burden and rescues synaptic and cognitive deficits that are hallmarks of AD.
First published on: April 06, 2010
Last modified on: May 17, 2024