The long-term objectives of this application are to understand the etiopathogenesis, facilitate the early diagnosis and perhaps suggest kinds of treatment of the dementia of the Alzheimer type (DAT), a devastating emerging epidemic which affects about 2.5 million American adults. To accomplish these aims, two monoclonal antibodies against tau protein and the peroxidase-antiperoxidase technique will be used in the following studies: 1. The evolution, distribution and morphology of tau immunoreactivity will be studied prospectively on autopsy tissue sections taken from throughout the central nervous system of DAT patients, especially those with short clinical history of dementia, so that clues regarding the pathogenesis and implications for the early diagnosis of DAt will hopefully become apparent. In addition, in order to test our hypothesis that tau accumulates before it becomes associated with the Alzheimer's abnormal filaments, tau in SDS extracts prepared from certain regions of DAT and age-matched control brains will be analyzed on nitrocellulose immunoblots and compared with the amount of tau immunoreactivity on adjacent tissue sections. 2. Since association of tau immunoreactivity with ribosomes might be a primary event, tau associated with ribosomes isolated from DAt and age- matched control brains will be analyzed on immunoblots. Also, the in vivo phosphorylation of 32 PO 4-labeled tau will be studied in ribosomes isolated from rat brains. 3. In order to gain further insight into the possible physiologic functions of tau an thus the pathogenesis of DAT, tau immunoreactivity will be studied by immunohistochemistry and immunoblotting of fetal, newborn, adult and aged rat brains in systemic rat organs that contain tau, and in the renal collecting duet epithelium of Brattleboro and hydropenic rats. 4. The hypothesis that the excessive tau immunolocalization in DAT brains may be the result of a response to stressful and noxious stimuli and, more specifically, a disturbance of a constitutive secretory and/or absorptive process will be tested by immunohistochemistry and immunoblotting of cultured fetal rat dorsal root ganglia and cerebral explants and in heat stressed rats. 5. The hypothesis that DAT might be caused by a serum factor will be tested by immunohistochemical and immunoblot analysis of tau in fetal rat dorsal root ganglia and cerebral explants cultured in feeding media containing serum or serum fractions obtained from DAt patients and age- matched controls.
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