Amyloid beta-protein induced electrophysiological changes are dependent on aggregation state: N-methyl-D-aspartate (NMDA) versus non-NMDA receptor/channel activation.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, however, the underlying mechanism driving this condition is unknown. Unexplored is the possibility that the time-dependent generation of different Abeta assemblies may underlie the pathogenic cascade with biophysically distinct structures interacting with unique biological targets. Thus, the presence of subtle alterations in synaptic function during the earliest clinical phase of AD may be mediated by diffusible assemblies of the amyloid beta-protein (Abeta). Using primary neocortical cultures, here we compare the synaptic responses induced by two different Abeta assemblies, protofibrils (PFs) and fibrils (FBs), and demonstrate for the first time that neuronal activation was selectively dependent on the assembly state of Abeta. PF-induced activity was specifically attenuated by the N-methyl-D-aspartate (NMDA) receptor antagonist, D-APV. In contrast, the non-NMDA glutamate receptor antagonist, NBQX, preferentially reduced FB-induced activity. In support, removal of Mg(2+) from the medium, which enhances NMDA channels, increased both PF- or FB-induced activation, but D-APV was more effective in attenuating PF-induced excitatory activity. These findings suggest that PFs may activate neurons differently than fibrils and lend support to the hypothesis that pre-fibrillar assemblies of Abeta may play an important role in the development of AD-type synaptic deficits.
Department of Medicine at Harvard Medical School, Division of Endocrinology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Chianping
C
Ye
Dominic M
DM
Walsh
Dennis J
DJ
Selkoe
Dean M
DM
Hartley
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D004347:Drug Interactions; D004622:Embryo, Mammalian; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019579:Neocortex / Q000166:cytology; D009474:Neurons / Q000145:classification / Q000187:drug effects* / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D011487:Protein Conformation; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D008869:Microtubule-Associated Proteins; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C056639:2-amino-5-phosphopentanoic acid; D014633:Valine