Abnormal neurites containing C-terminally truncated alpha-synuclein are present in Alzheimer's disease without conventional Lewy body pathology.

摘要

The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of alpha-synuclein (alpha-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25 of AD cases. C-terminally truncated forms of alpha-syn enhance the aggregation of alpha-syn in vitro. To investigate the presence of C-terminally truncated alpha-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated alpha-syn ending at residues 110 (alpha-syn110) and 119 (alpha-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that alpha-syn110 and alpha-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing alpha-syn140 also contained alpha-syn119; however, some aggregates contained alpha-syn119 without alpha-syn140, suggesting that alpha-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n = 27), LBV (n = 27), and AD (n = 19) and age-matched controls (n = 15) revealed that AD is also characterized by frequent abnormal neurites containing alpha-syn119. Notably, these neurites did not contain alpha-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing alpha-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.