Diffuse Lewy body disease (DLBD) is emerging as a distinctive and common entity. It is characterized pathologically by numerous senile plaques of the Alzheimer's disease type and widespread cortical and subcortical Lewy bodies (LBs). Clinically there is a varying degree of dementia and parkinsonian symptoms. Some recent studies indicate that this neuropathology is the second commonest finding in cases of dementia. Lewy bodies are intraneuronal cytoplasmic inclusions first described in 1912; their pathogenesis remains unknown. Recently we have preliminary results showing that antibodies raised to purified amyloid extracted from familial amyloidosis, Finnish type (FAF) immunoreact with LBs. This immunoreactivity can only be absorbed by the purified amyloid and is unaffected by antigens such as ubiquitin. FAF amyloid has been found to be a degradation product of gelsolin, an actin modulating protein. The amino acid sequence shows heterogeneity at the N-terminus and at position 15 where asparagine substitutes for aspartic acid. At the DNA level a guanine to adenine transition corresponding to nucleotide 654 of the human gelsolin has been found in all FAF patients tested so far. We plan to: (1) Perform an immunohistochemical survey on DLBD, Alzheimer's disease (AD) and Parkinson's disease (PD) cases with the anti-FAF antibody, as well as numerous other antibodies to evaluate the pattern of immunoreactivity. In addition, the immunoreactivity of """"""""eosinophilic bodies"""""""" reported in experimental models of PD will be studied, and compared to that noted in LBs. (2) Purify cortical LBs from a case of DLBD with biochemical methods, as well as using the anti-FAF antibodies for immunopurification. (3) Characterization of the composition of the purified LB preparation by the use of Western blotting and direct amino acid sequencing. (4) Eluting the protein bands which have been sequenced and using them to raise polyclonal antibodies. These will be assayed in LB containing material to verify that the material sequenced is contained in LBs. (5) Isolation of DNA from the brains of DLBD cases and familial PD to evaluate whether there is an abnormality in the gelsolin similar to that found in FAF or any other mutation. (6) Transmission studies with hamsters using the purified LB preparations. Together these studies will expand knowledge about LBs and the role gelsolin plays in their formation.
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