title: Rapid, reversible impairment of synaptic signaling in cultured cortical neurons by exogenously-applied amyloid-β.
abstract: Alzheimer's disease is accompanied by the accumulation of amyloid-β (Aβ) and the microtubule-associated protein tau. Aβ toxicity is dependent upon its form as well as concentration. Soluble Aβ oligomers, rather than the fibrillar forms that comprise senile plaques, represent the toxic form and are correlated with the extent of dementia. Since soluble Aβ perturbs synaptic function, we examined the impact of exogenously applied Aβ on signaling in neurons cultured on multi-electrode arrays. We observed that subcytotoxic levels (10 nm-5 μM) of human Aβ1-42 perturbed synaptic transmission within hours. This perturbation suggests that mild cognitive problems, perhaps undetected by traditional clinical approaches, can accompany critical accumulation of Aβ. This effect was prevented by the calcium chelator BAPTA, indicating a requirement for calcium for inhibition of signaling by Aβ. Aβ-induced inhibition of signaling was not prevented by application of MK-801 or nimodipine (antagonists of the NMDA receptor and L-type voltage-sensitive calcium channel, respectively) suggesting that Aβ may induce influx by either channel, or additional channels, or that neurons contained sufficient calcium to mediate the impact of Aβ. Signaling returned to original levels within 120 h after administration of a single dosage of Aβ, or within 24 h after replacement of medium with fresh medium lacking Aβ, suggesting that intervention to reduce Aβ levels at their first appearance may prevent permanent neurotoxicity.
authors: Center for Cellular Neurobiology and Neurodegeneration Research, Department of Biological Sciences, UMass Lowell, Lowell, MA 01854, USA.
authors: Sangmook
authors: S
authors: Lee
authors: Jill
authors: J
authors: Zemianek
authors: Thomas B
authors: TB
authors: Shea
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000473:pathology; D002614:Chelating Agents / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)