Normal human aging and two human dementias, Alzheimer's disease (AD) and Creutzfeldt-Jakob disease (CJD), are characterized by the accumulation of amyloid proteins in the brain. These amyloids are derived apparently from normal, but distinct, cellular precursor proteins. The presence of these precursors in circulating lymphocytes suggests that the study of these proteins in lymphocytes has relevance towards an understanding of cerebral amyloid formation; an event that occurs in both normal aging and to a pathological degree in AD and CJD. An intriguing possibility is that the formation of amyloid proteins occurs, at least in part, extra-neurally with secondary transport to and deposition within the brain. We propose to begin to test this hypothesis by investigating the biosynthesis and function in lymphocytes of two brain amyloid precursor proteins; the scrapie (CJD) amyloid cellular precursor protein (Cp33-37) and the AD amyloid precursor protein (APP). We have demonstrated that the AD-APP is present in normal human lymphocytes. Scrapie, an animal disease equivalent to CJD, is an invariably fatal encephalopathy of sheep that is transmissible to laboratory rodents. We have demonstrated in preliminary studies that Cp33- 37 is present on human and rodent lymphocytes, that it appears to modulate cell activation, and that its expression is increased with normal aging. Two experimental systems will be used in our work; (1) the Alzheimer's disease beta-amyloid protein betaA/4 and APP will be studied in normal human lymphocytes, lymphocytes from AD patients and controls, and selected lymphocytic cell lines; (2) the scrapie agent amyloid protein Sp33-37 and its cellular precursor Cp33-37 in scrapie-affected and normal hamsters. We propose three major aims: (1) The use of immunoaffinity purification, metabolic and immunochemical labelling, and techniques of protein chemistry and molecular biology to characterize the two amyloid precursor proteins in lymphocytes. (2) The use of specific antibodies in lymphocytic activation and proliferation assays to explore the normal function of Cp33-37 and APP in lymphocytes. (3) The exploration of lymphoid cells as a suitable tissue for diagnosing certain neurodegenerative diseases and for the study of amyloid precursor proteins in the normal aging process. This research is a major new direction in our long term project to investigate the conversion of normal brain proteins to pathologic and disease-associated amyloids.
