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The Journal of Neuroscience, November 15, 2000, 20(22):8384-8389
Selective and Protracted Apoptosis in Human Primary Neurons
Microinjected with Active Caspase-3, -6, -7, and -8
Yan
Zhang1, 3,
Cynthia
Goodyer2, and
Andréa
LeBlanc1, 3
Departments of 1 Neurology and Neurosurgery and
2 Pediatrics, McGill University, Montreal, Quebec, Canada
H3A 1W9, and 3 The Bloomfield Center for Research in Aging,
Lady Davis Institute for Medical Research, Jewish General Hospital,
Montreal, Quebec, Canada H3T 1E2
We have shown previously that caspase-6 is activated in serum
deprivation-mediated human neuronal cell death and correlates with
increased production of Alzheimer's disease (AD) amyloid  peptide
(A). Here, we show by direct microinjection of recombinant active
enzymes that caspase-6 (>0.5 pg/cell) induces a protracted course of
apoptosis in neurons in a caspase-specific, dose- and time-dependent
manner in the presence of serum. Only transient activation of caspase-6
is required to initiate apoptosis. Caspase-6 induces apoptosis directly
without the activation of other caspase effectors. Doses of caspase-6
of <0.25 pg/cell induce only 20% cell death within 16 d but
render neurons vulnerable to oxidative stress, indicating that caspase
activation affects neurons despite the absence of cell death. Caspase-3
induces neuronal apoptosis in 20% of the cells, whereas caspase-7 or
-8 do not induce apoptosis. In contrast, astrocytes undergo apoptosis
within 24 hr when microinjected with caspase-3 but not caspase-6, -7, or -8. These results show cell type-specific vulnerability to caspases
in the CNS. The results suggest that activation of caspases in human
neurons does not lead to an immediate and rapid process of cell death
but provokes a protracted form of apoptosis. Activation of caspases in
human neurons may participate in the long-term overproduction of A and other potential toxic fragments resulting from caspase-mediated proteolysis. These results are consistent with the protracted and
age-dependent nature of AD.
Key words:
caspase; primary neurons; Alzheimer's disease; oxidative
stress; astrocytes; apoptosis
Copyright © 2000 Society for Neuroscience 0270-6474/00/20228384-06$05.00/0
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