Grant: Project Grant

Microglia are a class of brain immune cells that play an important role in neuroinflammation, a protective response initiated to ward off toxins and pathogens. However, in Alzheimer's disease (AD), this response is subverted and becomes toxic leading to reduced communication between neurons, which is ultimately responsible for cognitive decline. During chronic inflammation, we know that the activity of a protein called PARP-1 is abnormally elevated in microglia. We also know that activation of PARP-1 promotes microglial responses that are detrimental to neurons. However, the mechanisms responsible for activating PARP-1 in microglia are poorly understood. Moreover, how PARP-1 mediated inflammation injures neurons is not known. Our past and recent findings suggests that amyloid beta, a toxic protein responsible for AD pathology, activates PARP- 1 activity through a pathway involving 1) a receptor for the neurotransmitter glutamate (NMDA receptor) and 2) TRPM2, an ion channel known to cause neuronal cell death and injury. By defining the mechanisms that activate and sustain this pathway, and in turn the mechanisms responsible for neuronal injury, we will identify prospective therapeutic targets able to prevent the neurotoxic effects of microglia. This would benefit AD patients, where neuroinflammation contributes to disease progression and severity.