Simultaneous Live Imaging of Multiple Endogenous Proteins Reveals a Mechanism for Alzheimer's-Related Plasticity Impairment

Cell Rep. 2019 Apr 16;27(3):658-665.e4. doi: 10.1016/j.celrep.2019.03.041.

Abstract

CaMKIIα is a central mediator of bidirectional synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD). To study how CaMKIIα movement during plasticity is affected by soluble amyloid-β peptide oligomers (Aβ), we used FingR intrabodies to simultaneously image endogenous CaMKIIα and markers for excitatory versus inhibitory synapses in live neurons. Aβ blocks LTP-stimulus-induced CaMKIIα accumulation at excitatory synapses. This block requires CaMKII activity, is dose and time dependent, and also occurs at synapses without detectable Aβ; it is specific to LTP, as CaMKIIα accumulation at inhibitory synapses during LTD is not reduced. As CaMKII movement to excitatory synapses is required for normal LTP, its impairment can mechanistically explain Aβ-induced impairment of LTP. CaMKII movement during LTP requires binding to the NMDA receptor, and Aβ induces internalization of NMDA receptors. However, surprisingly, this internalization does not cause the block in CaMKIIα movement and is observed for extrasynaptic, but not synaptic, NMDA receptors.

Keywords: CaMKII; FingR; LTD; LTP; NMDA-receptor; amyloid; excitatory synapse; inhibitory synapse; intrabody; trafficking.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / pharmacology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Disks Large Homolog 4 Protein / metabolism*
  • Female
  • Glutamic Acid / pharmacology
  • Hippocampus / cytology
  • Hippocampus / metabolism
  • Ionomycin / pharmacology
  • Long-Term Potentiation / drug effects
  • Long-Term Synaptic Depression / drug effects
  • Male
  • Membrane Proteins / metabolism*
  • N-Methylaspartate / pharmacology
  • Neuronal Plasticity*
  • Protein Transport / drug effects
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Synapses / metabolism

Substances

  • Amyloid beta-Peptides
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, rat
  • Membrane Proteins
  • Receptors, N-Methyl-D-Aspartate
  • gephyrin
  • Glutamic Acid
  • Ionomycin
  • N-Methylaspartate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2