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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS029793-03
Application #
3416684
Study Section
Neurology C Study Section (NEUC)
Project Start
1991-09-15
Project End
1995-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
de la Monte, S M; Garner, W; Wands, J R (1997) Neuronal thread protein gene modulation with cerebral infarction. J Cereb Blood Flow Metab 17:623-35
de la Monte, S M; Bloch, K D (1997) Aberrant expression of the constitutive endothelial nitric oxide synthase gene in Alzheimer disease. Mol Chem Neuropathol 30:139-59
Bloch, K D; Filippov, G; Sanchez, L S et al. (1997) Pulmonary soluble guanylate cyclase, a nitric oxide receptor, is increased during the perinatal period. Am J Physiol 272:L400-6
de la Monte, S M; Xu, Y Y; Wands, J R (1996) Modulation of neuronal thread protein expression with neuritic sprouting: relevance to Alzheimer's disease. J Neurol Sci 138:26-35
De La Monte, S M; Carlson, R I; Brown, N V et al. (1996) Profiles of neuronal thread protein expression in Alzheimer's disease. J Neuropathol Exp Neurol 55:1038-50
de la Monte, S M; Ng, S C; Hsu, D W (1995) Aberrant GAP-43 gene expression in Alzheimer's disease. Am J Pathol 147:934-46
Xu, Y Y; Bhavani, K; Wands, J R et al. (1995) Ethanol inhibits insulin receptor substrate-1 tyrosine phosphorylation and insulin-stimulated neuronal thread protein gene expression. Biochem J 310 ( Pt 1):125-32
de la Monte, S M; Bhavani, K; Xu, Y Y et al. (1995) Modulation of p36 gene expression in human neuronal cells. J Neurol Sci 128:122-33
Xu, Y Y; Bhavani, K; Wands, J R et al. (1995) Insulin-induced differentiation and modulation of neuronal thread protein expression in primitive neuroectodermal tumor cells is linked to phosphorylation of insulin receptor substrate-1. J Mol Neurosci 6:91-108
Xu, Y Y; Wands, J R; de la Monte, S M (1993) Characterization of thread proteins expressed in neuroectodermal tumors. Cancer Res 53:3823-9

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