Alzheimer’s disease (AD) is the most common form of dementia in people aged 65 years and older. More than 6.7 million people have AD in the United States alone. This proposal focuses on the identification and development of novel inhibitors of a therapeutic target protein, CD33, which is expressed exclusively in microglial cells in the brain and is associated with AD. The normal functions of microglial cells include degradation and clearance of toxic entities, including amyloid beta (Aβ) and phospho tau protein (pTau) aggregates, the two major hallmarks of AD. Griciuc et al. and others have shown that AD brains have very high expression of the full-length CD33 protein, and the latter inhibits microglial functions—and thereby, the clearance of the amyloid beta and pTau aggregates. A protective CD33 isoform or type also is known to confer protection from the disease. A synthetic compound has been identified that modulates the CD33 gene to increase the protective isoform. The goal of this study is to discover CD33 inhibitors and modulators that will inhibit the effects of the disease-associated CD33 isoform and enhance the effects of the protective CD33 isoform. In both scenarios, degradation and cleansing of the neurotoxic protein aggregates in AD brains will be facilitated. To identify CD33 inhibitors, we will start with identifying hit compounds using two complementary methods—conventional high-throughput screening and fragment-based screening, both known to provide true hits and modify the hits to discover potent lead candidates. The CD33 modulators that favor expression of the protective CD33 isoform will be developed by modifying the known hit. The proposed studies will be performed in collaboration with Drs. Ana Griciuc and Rudolph E. Tanzi at Massachusetts General Hospital. At the end of this study, we anticipate we will identify and select for further development one each of the potent and selective CD33 inhibitor and CD33 gene modulator as the tool candidates.