Abstract
Fibrillar amyloid beta (Abeta) peptides are major constituents of senile plaques in Alzheimer disease (AD) brain and cause neuronal apoptosis in vitro. Bax and caspase-3 have been implicated in the pathogenesis of AD and are components of a well-defined molecular pathway of neuronal apoptosis. To determine whether Abeta-induced neuronal apoptosis involves bax and/or caspase-3 activation, we examined the effect of Abeta on wild-type, bax-deficient, and caspase-3-deficient telencephalic neurons in vitro. In wild-type cultures, Abeta produced time- and concentration-dependent caspase-3 activation, apoptotic nuclear changes, and neuronal death. These neurotoxic effects of Abeta were not observed in bax-deficient cultures. Caspase-3 deficiency, or pharmacological inhibition of caspase activity, prevented caspase-3 activation and blocked the appearance of apoptotic nuclear features but not Abeta-induced neuronal death. Neither calpain inhibition nor microtubule stabilization with Taxol protected telencephalic neurons from Abeta-induced caspase activation or apoptosis. These results have potential implications regarding the underlying pathophysiology of AD and towards AD treatment strategies.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amino Acid Chloromethyl Ketones / pharmacology
-
Amyloid beta-Peptides / metabolism*
-
Amyloid beta-Peptides / pharmacology
-
Animals
-
Apoptosis / drug effects
-
Apoptosis / genetics
-
Caspase 3
-
Caspase Inhibitors
-
Caspases / deficiency
-
Caspases / genetics
-
Caspases / metabolism*
-
Cell Death / drug effects
-
Cell Death / genetics
-
Cells, Cultured
-
Cysteine Proteinase Inhibitors / pharmacology
-
Dose-Response Relationship, Drug
-
Female
-
Glycoproteins / pharmacology
-
In Situ Nick-End Labeling
-
Male
-
Mice
-
Mice, Knockout
-
Microtubule-Associated Proteins / metabolism
-
Microtubules / metabolism
-
Neurons / cytology
-
Neurons / drug effects
-
Neurons / enzymology*
-
Paclitaxel / pharmacology
-
Proto-Oncogene Proteins / deficiency
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism*
-
Proto-Oncogene Proteins c-bcl-2*
-
Telencephalon / cytology
-
Telencephalon / drug effects
-
Telencephalon / enzymology
-
bcl-2-Associated X Protein
Substances
-
Amino Acid Chloromethyl Ketones
-
Amyloid beta-Peptides
-
Bax protein, mouse
-
Caspase Inhibitors
-
Cysteine Proteinase Inhibitors
-
Glycoproteins
-
Microtubule-Associated Proteins
-
Proto-Oncogene Proteins
-
Proto-Oncogene Proteins c-bcl-2
-
bcl-2-Associated X Protein
-
butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone
-
calpain inhibitors
-
Casp3 protein, mouse
-
Caspase 3
-
Caspases
-
Paclitaxel