Abnormal neurites containing C-terminally truncated alpha-synuclein are present in Alzheimer's disease without conventional Lewy body pathology.
The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of α-synuclein (α-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 α-syn enhance the aggregation of α-syn in vitro. To investigate the presence of C-terminally truncated α-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated α-syn ending at residues 110 (α-syn110) and 119 (α-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that α-syn110 and α-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing α-syn140 also contained α-syn119; however, some aggregates contained α-syn119 without α-syn140, suggesting that α-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 α-syn119. Notably, these neurites did not contain α-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing α-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.
Graduate Program in Molecular Biophysics, Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Karen A
KA
Lewis
Yang
Y
Su
Olina
O
Jou
Caroline
C
Ritchie
Chan
C
Foong
Linda S
LS
Hynan
Charles L
CL
White
Philip J
PJ
Thomas
Kimmo J
KJ
Hatanpaa
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000378:metabolism / Q000473:pathology*; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D016501:Neurites / Q000378:metabolism* / Q000473:pathology*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D046888:Tissue Array Analysis; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism*
D050505:Mutant Proteins; D020033:Protein Isoforms; D051844:alpha-Synuclein