TY - JOUR
T1 - Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12
AU - Chan, Sic L.
AU - Culmsee, Carsten
AU - Haughey, Norman
AU - Klapper, Wolfram
AU - Mattson, Mark P.
PY - 2002
Y1 - 2002
N2 - Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.
AB - Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca2+ levels, induction of p53, upregulation of the Ca2+-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca2+ chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca2+ from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.
KW - Alzheimer's disease
KW - Endoplasmic reticulum
KW - Hippocampal neurons
KW - PARP
KW - Topoisomerase
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UR - http://www.scopus.com/inward/citedby.url?scp=0036452908&partnerID=8YFLogxK
U2 - 10.1006/nbdi.2002.0542
DO - 10.1006/nbdi.2002.0542
M3 - Article
C2 - 12460542
AN - SCOPUS:0036452908
SN - 0969-9961
VL - 11
SP - 2
EP - 19
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -