Alzheimer's disease (AD) poses a growing challenge to the health care systems and economies worldwide. In the United States alone, more than five million people are suffering from this devastating disease and this number is expected to triple in the next 40 years due to our aging population. The fact that there is no effective treatment available to slow down or reverse the disease underscores the great need to develop new therapeutic strategies to prevent and/or delay AD. Recent studies discovered that a variation in the gene of clusterin (also known as apoJ) is significantly associated with AD. Similar to a major AD-related protein apoE, apoJ is a multifunctional protein. In addition to playing an important role in cholesterol/lipid metabolism as a component of high-density lipoproteins (HDL) in the brain, apoJ has a high affinity for binding amyloid-beta protein (Abeta), a recognized culprit of AD, and is found in amyloid plaques. ApoJ can also inhibit Abeta aggregation and facilitate the clearance of Abeta, as well as modulating inflammatory and immune functions. Thus, apoJ serves as a promising target for developing novel therapeutic agents for AD. A small peptide derived from apoJ has been found to mimic the properties of apoJ; it enhances the anti-inflammatory function of HDL and dramatically reduces vascular lesions in animal models (mice and monkeys). In preliminary studies, we found that the apoJ mimetic peptide protects neuronal cells from Abeta toxicity, enhances neuronal transmission in mouse brain slices, improves HDL function in a mouse model of AD, and crosses the human blood-brain barrier (BBB) in vitro. The present study proposes to investigate the potential of the apoJ peptide on mitigating AD-like symptoms and brain lesions in a mouse model of AD. Our ultimate goal is to establish the apoJ mimetic peptide as an effective anti-AD agent.