DNA damage and activated caspase-3 expression in neurons and astrocytes: evidence for apoptosis in frontotemporal dementia.
Frontotemporal dementia (FTD) is a neurodegenerative disease which affects mainly the frontal and anterior temporal cortex. It is associated with neuronal loss, gliosis, and microvacuolation of lamina I to III in these brain regions. In previous studies we have described neurons with DNA damage in the absence of tangle formation and suggested this may result in tangle-independent mechanisms of neurodegeneration in the AD brain. In the present study, we sought to examine DNA fragmentation and activated caspase-3 expression in FTD brain where tangle formation is largely absent. The results demonstrate that numerous nuclei were TdT positive in all FTD brains examined. Activated caspase-3 immunoreactivity was detected in both neurons and astrocytes and was elevated in FTD cases as compared to control cases. A subset of activated caspase-3-positive cells were also TdT positive. In addition, the cell bodies of a subset of astrocytes showed enlarged, irregular shapes, and vacuolation and their processes appeared fragmented. These degenerating astrocytes were positive for activated caspase-3 and colocalized with robust TdT-labeled nuclei. These findings suggest that a subset of astrocytes exhibit degeneration and that DNA damage and activated caspase-3 may contribute to neuronal cell death and astrocyte degeneration in the FTD brain. Our results suggest that apoptosis may be a mechanism of neuronal cell death in FTD as well as in AD (228).
Su
J H
JH
Institute for Brain Aging and Dementia, University of California, Irvine, Irvine, California 92697, USA.
Nichol
K E
KE
Sitch
T
T
Sheu
P
P
Chubb
C
C
Miller
B L
BL
Tomaselli
K J
KJ
Kim
R C
RC
Cotman
C W
CW
D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001253:Astrocytes / Q000201:enzymology* / Q000473:pathology; D001526:Behavioral Symptoms / Q000175:diagnosis; D001921:Brain / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus / Q000201:enzymology / Q000473:pathology; D004249:DNA Damage; D053938:DNA Fragmentation; D003704:Dementia / Q000175:diagnosis / Q000473:pathology* / Q000503:physiopathology*; D017809:Fatal Outcome; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D016501:Neurites / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000201:enzymology* / Q000473:pathology; D017966:Pyramidal Cells / Q000201:enzymology / Q000473:pathology; D013702:Temporal Lobe / Q000201:enzymology / Q000473:pathology
D005904:Glial Fibrillary Acidic Protein; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases