Plasma phospholipid transfer protein (PLTP) is one of the key proteins in lipid and lipoprotein metabolism.We examined PLTP distribution in human brain using PLTP mRNA dot-blot, Northern blot, immunohistochemistry (IHC), Western blot, and phospholipid transfer activity assay analyses. PLTP mRNA of 1.8 kb was widely distributed in all the examined regions of the central nervous system at either comparable or slightly lower levels than in the other major organs, depending on the region. Cerebrospinal fluid phospholipid transfer activity represented 15% of the plasma activity, indicating active PLTP synthesis in the brain. The human brain is an organ of a very complex structure, function, and composition, and its rich lipid content sets it apart from other major organs and systems. Lipids represent approximately half of the brain's dry weight, with phospholipids and cholesterol among the main constituents (1, 2). Although the human central nervous system (CNS) accounts for only ف 2% of the total body mass, it contains over 20% of total body unesterified cholesterol (3). While some aspects of CNS lipid metabolism are similar to the lipid metabolism of other peripheral organs (4), there are also many specific differences. Normally, adult human brain contains virtually no cholesterol esters or triglycerides (1). Distribution and quantity of the various classes and types of lipids, some of which are found exclusively in the brain, vary based on the brain region and age (1, 5). Lipids serve not only as structural components of the cell membranes but also act as precursors, biomessengers, and signal transduction molecules.Despite the importance of lipids for brain function, our current knowledge of lipid metabolism and lipid transfer proteins in the human brain is surprisingly limited. Evidence has been provided to suggest that cholesteryl ester transfer protein (CETP) is synthesized and secreted in the brain (6), and its localization in brain astrocytes has been reported (7). However, others have not been able to demonstrate any CETP or cholesteryl ester transfer activity in human brain (8). Phospholipid transfer protein (PLTP) is Abbreviations: ABC, avidin biotin complex; AD, Alzheimer's disease; CNS, central nervous system; CSF, cerebrospinal fluid; DAB, 3,3 Ј -diaminobenzidine; FFPE, formalin-fixed, paraffin-embedded; GFAP, glial fibrillary acidic protein; HRP, horseradish peroxidase; IHC, immunohistochemistry; MAb, monoclonal antibody; MBP, myelin basic protein; PLTA, phospholipid transfer protein activity; PLTP, phospholipid transfer protein.1 Qualified investigators can obtain anti-PLTP monoclonal antibodies 1 and 4 by contacting Dr. Santica M. Marcovina,