By 2050 it is estimated that there will be 13.8 million individuals in the US with Alzheimer's disease (AD), at a cost of over $1.2 trillion per yr, if no disease-modifying therapy is developed. The relative contributions of the AD defining pathological markers, amyloid and hyperphosphorylated tau, to cognitive dysfunction remains controversial, but studies in both AD patients and transgenic mouse models of AD, have shown that amyloid is necessary but not sufficient for the development of cognitive loss which is the key clinical target of AD. There is a growing consensus that it is the response of glial cells in the brain to amyloid that is relevant to neuronal damage and thus cognitive impairment. The capacity of these cells to phagocytose and clear amyloid and perhaps other deleterious material in the brain may have a substantial influence on the initiation and progression of the disease. The complement cascade, a powerful effector mechanism of the immune system that is directly activated by fibrillar A? (fA?), can both enhance clearance and induce inflammation. In addition, complement activation dependent excessive synapse pruning occurs in models of AD and other neurological disorders, and is postulated to contribute to the loss of cognition. Our data demonstrate that pharmacologic inhibition or genetic deletion of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses cognitive loss in mouse models of Alzheimer's disease/amyloidosis. This study proposes to investigate the effect of a C5a receptor antagonist on inflammation- and clearance-related gene expression (using single cell RNA-seq to evaluate multiple cell types affected), protein expression and synaptic density (via super resolution microscropy) in order to determine if C5aR1 plays a direct or indirect role in neuronal damage and whether C5aR1 antagonists may be promising therapeutic candidates for future clinical trials in humans to prevent cognitive impairment.
In the U.S. alone, the cost of caring for an estimated 5.4 million people afflicted with Alzheimer's Disease (AD), is now over 240 billion dollars per year. Studies in mouse models in this lab have discovered that deletion of the gene for a proinflammatory receptor normally activated in AD, suppresses neurite loss and cognitive loss associated with AD pathology. In addition, a drug-like inhibitor of the receptor blunts AD pathology and avoids cognitive loss in mouse models. This proposal will investigate the mechanistic pathway from inhibition of the receptor to preservation of cognitive function, to provide further justification to move this therapeutic lead toward clinical trials for slowing the progression of cognitive loss in AD.
