Amyloid-beta induces a caspase-mediated cleavage of P2X4 to promote purinotoxicity.
Overproduction of the beta-amyloid fragment 1-42 (A beta(1-42)) is thought to contribute to synaptic dysfunction and neuronal death in Alzheimer's disease. Mounting evidence suggests that purinergic receptors play critical roles in synaptic plasticity and neuronal survival, but the potential involvement of these receptors in A beta(1-42)-induced synaptic dysfunction and neuronal death has not been addressed. Here we report that A beta(1-42) promoted accumulation of the calcium-permeable purinergic receptor P2X4 in neurons. We also report evidence that A beta(1-42) induced a caspase-3-mediated cleavage of the receptor that slowed channel closure times and prevented agonist-induced internalization of the receptor. Molecular interference to reduce the expression of P2X4 in primary rodent neurons attenuated A beta(1-42)-induced neuronal death while induced expression of P2X4 in a neuronal cell line that does not normally express P2-receptors enhanced the toxic effect of A beta(1-42). Together these findings suggest that A beta(1-42)-induced synaptic dysfunction and neuronal death may involve perturbations in P2X4 purinergic receptors.
Varma
R
R
Department of Neurology, Johns Hopkins, University School of Medicine, Meyer 6-109, 600 N. Wolfe St., Baltimore, MD 21287, USA.
Chai
Y
Y
Troncoso
J
J
Gu
J
J
Xing
H
H
Stojilkovic
S S
SS
Mattson
M P
MP
Haughey
N J
NJ
D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000633:toxicity*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism*; D058848:Receptors, Purinergic P2X4; D013569:Synapses / Q000378:metabolism
D016229:Amyloid beta-Peptides; C548226:P2RX4 protein, human; D010446:Peptide Fragments; D011687:Purines; D034741:RNA, Small Interfering; D018048:Receptors, Purinergic P2; D058848:Receptors, Purinergic P2X4; C075222:amyloid beta-protein (1-42); D053148:Caspase 3; D002118:Calcium