Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disease that impairs memory and causes cognitive and psychiatric deficits. AD affects over 50 million people and as the number of patients increases exponentially each year, the need for effective therapeutics is becoming more urgent. The etiology underlying AD remains poorly understood; however, evidence from AD patients strongly suggest a role for inflammation in the onset and progression of the disease.

The complement system, an important part of our immune system, can be activated by fibrillar Aß and phospho-Tau, both neuropathological hallmarks in AD brains. Activation of the complement system can generate C5a, which binds to its receptor C5aR1 and contributes to neuroinflammation. In addition, there is evidence that during AD there is an excessive loss of synapses, which are the basic structure that allow neurons to communicate with one another and so, they are extremely necessary for the correct functioning of the brain. During Alzheimer’s, this excessive loss of synapses has been widely shown to be dependent on initial complement activation, which trigger the ingestion of synapses by microglial cells. However, the mechanisms that regulates synaptic pruning during AD are still not well understood and, therefore our goal is to test whether C5a-C5aR1 signaling (a downstream effector of complement activation) is actively contributing to synaptic engulfment by microglia in AD, further contributing to synaptic loss and memory deficits. The expected results from this project will provide additional insight on the value of C5aR1 antagonists as a novel candidate therapeutic for human AD.