alpha-Synuclein is a presynaptic terminal protein that accumulates abnormally in plaques in Alzheimer's disease (AD), in Lewy bodies in Lewy body disease (LBD) and in filamentous inclusions in multiple system atrophy. Since it has been previously shown that proteinase K or formic acid pretreatment enhances alpha-synuclein immunoreactivity in Lewy bodies and plaques, we hypothesized that the immunoreactivity in tangles, glial cells and Pick bodies might be revealed by such pretreatment. Brain sections from patients with AD, LBD, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Pick's disease were pretreated with proteinase K or formic acid and immunostained with antibodies against the N-terminal, C-terminal or non-amyloid beta component of AD amyloid (NAC) regions of alpha-synuclein. This study showed that after proteinase K (but not formic acid) pretreatment the anti-C terminus antibody immunostained neurofibrillary tangles of AD, PSP and CBD, and glial inclusions of PSP and CBD, as well as Pick bodies. Western blot analysis confirmed that in cases other than LBD, the anti-C terminus antibodies also recognized the native alpha-synuclein band and no cross-reactive bands were observed. In contrast, in LBD, after formic acid pretreatment with the anti-NAC antibody astroglial cells and granular neurons were immunostained. The N-terminal region antibody only recognized the lesions in LBD cases and not those of other neurodegenerative disorders. These results support the view that different fragments of alpha-synuclein might play an important role in the pathogenesis of several neurodegenerative disorders.