ABNORMAL DISTRIBUTION OF THE NON-A-BETA COMPONENT OF ALZHEIMERS-DISEASE AMYLOID PRECURSOR ALPHA-SYNUCLEIN IN LEWY BODY DISEASE AS REVEALED BY PROTEINASE-K AND FORMIC-ACID PRETREATMENT/

The precursor of the non-A beta component of Alzheimer's disease amylo id (NACP) (also known as alpha-synuclein) is a presynaptic terminal mo lecule that abnormally accumulates in the plaques of Alzheimer's disea se (AD) and in the Lewy bodies (LBs) of Lewy body variant of AD, diffu se Lewy body disease, and Parkinson's disease. To better understand th e distribution of NACP/alpha-synuclein and its fragments in the LB-bea ring neurons and neurites, as well as to clarify the patterns of NACP/ (alpha-asynuclein compartmentalization, we studied NACP/a-synuclein im munoreactivity using antibodies against the C-terminal, N-terminal, an d NAC regions after Proteinase K and formic acid treatment in the cort ex of patients with LBs. Furthermore, studies of the subcellular local ization of NACP/alpha-synuclein within LB-bearing neurons were perform ed by immunogold electron microscopy. These studies showed that the N- terminal antibody immunolabeled the LBs and dystrophic neurites with g reat intensity and, to a lesser extent, the synapses. In contrast, the G-terminal antibody strongly labeled the synapses and, to a lesser ex tent, the LBs and dystrophic neurites. Whereas Proteinase K treatment enhanced NACP/alpha-synuclein immunoreactivity with the G-terminal ant ibody, it diminished the N-terminal NACP/a-synuclein immunoreactivity. Furthermore, formic acid enhanced LB and dystrophic neurite labeling with both the C- and N-terminal antibodies. In addition, whereas witho ut pretreatment only slight anti-NAG immunoreactivity was found in the LBs, formic acid pretreatment revealed an extensive anti-NAG immunost aining of LBs, plaques, and glial cells. Ultrastructural analysis reve aled that NACP/alpha-synuclein immunoreactivity was diffusely distribu ted within the amorphous electrodense material in the LBs and as small clusters in the filaments of LBs and neurites. These results support the view that aggregated NACP/alpha-synuclein might play an important role in the pathogenesis of disorders associated with LBs.