Alzheimer's disease is the most important cause of dementia in the United States, afflicting 15% of individuals over the age of 60. There is no effective treatment and in vivo diagnosis is based entirely upon clinical observations and exclusion of other treatable diseases. In the last 3 decades a great deal of effort has been devoted to defining the pathology and refining criteria for diagnosis. Although very important in many respects, the descriptive information yielded by these approaches has provided little information on pathogenesis. In this regard, we have identified an abundant exocrine pancreatic secretory thread protein that undergoes pH-dependent insoluble fibril formation, imparting ultrastructural features highly reminiscent of the paired-helical filaments of Alzheimer's disease. We now have cloned a full-length cDNA coding for this protein. To our surprise, we found high high-level expression of an antigenically related molecule termed neuronal thread protein (NTP) in Alzheimer's disease and Down's syndrome brains compared with aged controls with the distribution of immunoreactivity corresponding to neurofibrillary tangles and neuropil threads, the principal lesions correlated with dementia. Using molecular approaches we detected over-expressed as well as abnormal size NTP mRNA transcripts in Alzheimer's disease brains suggesting possible mutation or aberrant regulation. We also observed that NTP over- expression in Alzheimer's disease may be detectable by assay of cerebrospinal (CSF). Other preliminary studies demonstrated that the NTP gene is expressed at high levels in zones immediately adjacent to small infarcts where growth, repair and the structural plasticity required for learning and establishing new memory. We believe that the aberrant expression of NTP may be important to Alzheimer's disease and wish to consolidate and extend our observations with this proposed research. Our objectives are to examine the specificity of NTP over-expression in Alzheimer's disease by studying NTP expression in other neurodegenerative diseases; determine the ultrastructural localization of NTP in relation to paired-helical filaments and neuropil threads; perform CSF analyses to refine the assay and thus potentially develop an in vivo diagnostic test for Alzheimer's disease; clone NTP from a human brain cDNA library and determine the chromosome localization of the gene; characterize Alzheimer's disease NTP mRNA and accumulated protein in CNS neurons; explore the role of NTP in neuronal development using animal models and in vitro transfection studies; identify the potential molecular defect associated with Alzheimer's disease NTP transcripts using in vitro transfection, in vitro translation and peptide mapping assays. We expect that the studies outlined in the present application will help define the molecular and cellular role of this new and novel protein in the neuropathogenesis of Alzheimer's disease.
Showing the most recent 10 out of 13 publications
