Pathological heterogeneity of frontotemporal lobar degeneration with ubiquitin-positive inclusions delineated by ubiquitin immunohistochemistry and novel monoclonal antibodies.
Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) is a common neuropathological subtype of frontotemporal dementia. Although this subtype of frontotemporal dementia is defined by the presence of ubiquitin-positive but tau- and alpha-synuclein-negative inclusions, it is unclear whether all cases of FTLD-U have the same underlying pathogenesis. Examination of tissue sections from FTLD-U brains stained with anti-ubiquitin antibodies revealed heterogeneity in the morphological characteristics of pathological inclusions among subsets of cases. Three types of FTLD-U were delineated based on morphology and distribution of ubiquitin-positive inclusions. To address the hypothesis that FTLD-U is pathologically heterogeneous, novel monoclonal antibodies (mAbs) were generated by immunization of mice with high molecular mass (Mr > 250 kd) insoluble material prepared by biochemical fractionation of FTLD-U brains. Novel mAbs were identified that immunolabeled all of the ubiquitin-positive inclusions in one subset of FTLD-U cases, whereas other mAbs stained the ubiquitin-positive inclusions in a second subset of cases. These novel mAbs did not stain inclusions in other neurodegenerative disorders, including tauopathies and alpha-synucleinopathies. Therefore, ubiquitin immunohistochemistry and the immunostaining properties of the novel mAbs generated here suggest that FTLD-U is pathologically heterogeneous. Identification of the disease proteins recognized by these mAbs will further advance understanding of molecular substrates of FTLD-U neurodegenerative pathways.
Sampathu
Deepak M
DM
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 3600 Spruce St., 3rd Floor Maloney Bldg., Philadelphia, PA 19104, USA.
Neumann
Manuela
M
Kwong
Linda K
LK
Chou
Thomas T
TT
Micsenyi
Matthew
M
Truax
Adam
A
Bruce
Jennifer
J
Grossman
Murray
M
Trojanowski
John Q
JQ
Lee
Virginia M-Y
VM
D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D003704:Dementia / Q000473:pathology*; D005260:Female; D005625:Frontal Lobe / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D002479:Inclusion Bodies / Q000737:chemistry*; D008297:Male; D051379:Mice; D008875:Middle Aged; D013702:Temporal Lobe / Q000473:pathology*; D025801:Ubiquitin / Q000032:analysis* / Q000276:immunology
D000911:Antibodies, Monoclonal; D025801:Ubiquitin