ALTERED PRESYNAPTIC PROTEIN NACP IS ASSOCIATED WITH PLAQUE-FORMATION AND NEURODEGENERATION IN ALZHEIMERS-DISEASE

We have recently identified in the brain tissue of patients afflicted with Alzheimer's disease (AD), the non-A beta component of AD amyloid (NAC) as a new constituent of amyloid. NAC is derived from a larger pr ecursor, NACP, a presynaptic protein. To better understand the role of NACP/NAC in the pathogenesis of AD, we used semiquantitative immunobl otting and combined double-immunocytochemistry/laser scanning confocal microscopy to study the concentration and distribution of NACP/NAC in human brain, and compared them to the concentration and distribution of the presynaptic marker synaptophysin and the amyloid marker A beta. The semiquantitative immunoblotting demonstrated that the NACP concen tration is slightly increased in the AD frontal cortex without statist ical significance, whereas synaptophysin was reduced in its levels in AD. Consequently, the proportion of NACP/synaptophysin was more than d ouble in the AD frontal cortex as compared with controls, In the AD ne ocortex, NACP was colocalized with similar to 80% of the synaptophysin -immunoreactive structures (presumably the presynaptic terminals) and with the dystrophic neuritic component of the plaques Computer-aided a nalysis showed that numbers of NACP-immunoreactive structures along sy naptophysin-immunoreactive structures were significantly diminished (3 0 to 40%) in AD. Although the overall numbers of NACP-positive structu res were decreased, there was a significant increase in the intensity of NACP-immunoreactivity per structure in AD. This increased intensity of NACP immunoreactivity per structure in AD was not observed with an ti-synaptophysin, consistent with immunoblotting-based quantification. Antibodies against NAC immunoreacted with amyloid in 35% of the diffu se plaques and 55% of the mature plaques. Normal aged control brains c ontaining small groups of diffuse plaques were negative with anti-NAC, Double-immunolabeling studies with AP antibodies showed that NAC immu noreactivity is more abundant in the center portion of amyloid rather than in the periphery, These studies suggest that there is a connectio n between metabolism of presynaptic proteins and amyloid formation, an d that NAC might follow diffuse A beta accumulation resulting in the f ormation of compact amyloid and mature plaques.