Our current inability to prevent or delay Alzheimer’s disease (AD) and the expected increase in the prevalence of AD are predicted to give rise to a global AD pandemic. We recently have identified a novel pathway for amyloid beta (Abeta) clearance in the aging brain that is highly relevant to AD pathogenesis. In a very large family-based, genome-wide association study, we identified CD33 as a novel late-onset AD risk factor. CD33 encodes a transmembrane sialic acid-binding immunoglobulin-like lectin that regulates innate immunity.
We found that CD33 is specifically expressed in microglial cells and exhibits an increased expression in AD. Using microglial cell cultures, we showed that CD33 inhibits uptake and clearance of Abeta42, a process that requires the sialic acid-binding domain of CD33. CD33 knockout led to a marked reduction in insoluble Abeta42 levels and amyloid plaque burden in mouse models of AD. We also found that CD33 knockout in AD mice results in skewing of adult microglia from the M1 (pro-inflammatory, neurotoxic) to the M2 (pro-phagocytic, neuroprotective) activation phenotype. Thus, CD33 activity in microglial cells promotes Abeta pathology, and CD33 has emerged as a novel target for drug development in AD.
Here, we propose to inhibit CD33 activity 1) to induce uptake and clearance of Abeta42, and 2) to enhance skewing of microglia from the pro-inflammatory M1 toward the pro-phagocytic M2 activation state. We will identify and validate effective CD33 inhibitors by performing an unbiased high-throughput screen of 1,280 small molecules in microglial cells. These compounds are from Prestwick Chemical and were approved by the U.S. Food and Drug Administration and other agencies. We also will develop CD33 inhibitors by screening CD33-specific antibodies for their ability to inhibit CD33 function in microglial cell-based assays. Successful compounds and CD33-specific antibodies that inhibit CD33 activity in Abeta clearance and M1/M2 cytokine release assays will be further tested in mice. These studies might result in a novel and powerful therapeutic approach for AD.