Caspase Activation and Caspase-Mediated Cleavage of APP Is Associated with Amyloid β-Protein-Induced Synapse Loss in Alzheimer's Disease

Cell Rep. 2020 Jun 30;31(13):107839. doi: 10.1016/j.celrep.2020.107839.

Abstract

Amyloid β-protein (Aβ) toxicity is hypothesized to play a seminal role in Alzheimer's disease (AD) pathogenesis. However, it remains unclear how Aβ causes synaptic dysfunction and synapse loss. We hypothesize that one mechanism of Aβ-induced synaptic injury is related to the cleavage of amyloid β precursor protein (APP) at position D664 by caspases that release the putatively cytotoxic C31 peptide. In organotypic slice cultures derived from mice with a knock-in mutation in the APP gene (APP D664A) to inhibit caspase cleavage, Aβ-induced synaptic injury is markedly reduced in two models of Aβ toxicity. Loss of dendritic spines is also attenuated in mice treated with caspase inhibitors. Importantly, the time-dependent dendritic spine loss is correlated with localized activation of caspase-3 but is absent in APP D664A cultures. We propose that the APP cytosolic domain plays an essential role in Aβ-induced synaptic damage in the injury pathway mediated by localized caspase activation.

Keywords: APP; APP C31; Alzheimer’s disease; caspase; synaptic injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism*
  • Amyloid beta-Protein Precursor / toxicity
  • Animals
  • Caspase 3 / metabolism*
  • Caspase Inhibitors / pharmacology
  • Dendritic Spines / metabolism
  • Enzyme Activation / drug effects
  • Gene Knock-In Techniques
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Neuroprotection / drug effects
  • Synapses / metabolism*

Substances

  • Amyloid beta-Protein Precursor
  • Caspase Inhibitors
  • Caspase 3