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, and that the capacity 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. Our data demonstrate that pharmacologic inhibition or genetic deletion of C5aR1, a receptor for the complement activation proinflammatory fragment, C5a, suppresses neurite and cognitive loss in mouse models of Alzheimer's disease/amyloidosis. The effects of blocking this C5a receptor interaction on astrocyte activation, inflammatory and clearance related gene expression, neuronal integrity and synaptic density are proposed in two aims here with the ultimate goal of determining mechanistic steps between activation of C5aR1 and loss of neuronal function, as well as the potential for C5aR1 antagonists as therapeutic candidates for clinical trials in humans to prevent cognitive impairment. In a third aim, we proposed to use a newly generated mouse with a floxed C5aR1, to temporally and cell specifically ablate the receptor and assess gene expression, neuronal integrity and function in an AD mouse model, to more closely mimic the adult inhibition of this receptor that would occur with receptor antagonist treatment of individuals with or at risk for AD. Selective modulation of complement activation products or their receptors may be an optimal strategy for retaining the neuroprotective and phagocytic functions of complement components, as well as systemic protection from pathogens lysis, while dampening induced inflammatory damage. Importantly, blockage of this ligand-receptor system has not shown adverse effects in humans, suggesting that C5aR1-targeted therapeutics for AD may be safely administered.
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.
