Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease

Am J Pathol. 2008 Sep;173(3):665-81. doi: 10.2353/ajpath.2008.071176. Epub 2008 Aug 7.


Mechanisms of neuronal loss in Alzheimer's disease (AD) are poorly understood. Here we show that apoptosis is a major form of neuronal cell death in PS/APP mice modeling AD-like neurodegeneration. Pyknotic neurons in adult PS/APP mice exhibited apoptotic changes, including DNA fragmentation, caspase-3 activation, and caspase-cleaved alpha-spectrin generation, identical to developmental neuronal apoptosis in wild-type mice. Ultrastructural examination using immunogold cytochemistry confirmed that activated caspase-3-positive neurons also exhibited chromatin margination and condensation, chromatin balls, and nuclear membrane fragmentation. Numbers of apoptotic profiles in both cortex and hippocampus of PS/APP mice compared with age-matched controls were twofold to threefold higher at 6 months of age and eightfold higher at 21 to 26 months of age. Additional neurons undergoing dark cell degeneration exhibited none of these apoptotic features. Activated caspase-3 and caspase-3-cleaved spectrin were abundant in autophagic vacuoles, accumulating in dystrophic neurites of PS/APP mice similar to AD brains. Administration of the cysteine protease inhibitor, leupeptin, promoted accumulation of autophagic vacuoles containing activated caspase-3 in axons of PS/APP mice and, to a lesser extent, in those of wild-type mice, implying that this pro-apoptotic factor is degraded by autophagy. Leupeptin-induced autophagic impairment increased the number of apoptotic neurons in PS/APP mice. Our findings establish apoptosis as a mode of neuronal cell death in aging PS/APP mice and identify the cross talk between autophagy and apoptosis, which influences neuronal survival in AD-related neurodegeneration.

Publication types

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

MeSH terms

  • Alzheimer Disease / pathology*
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Autophagy / physiology*
  • Blotting, Western
  • Brain / drug effects
  • Brain / pathology*
  • Caspase 3 / metabolism
  • Cysteine Proteinase Inhibitors / administration & dosage
  • Disease Models, Animal
  • Enzyme Activation / physiology
  • Female
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Injections, Intraventricular
  • Leupeptins / administration & dosage
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Neurons / drug effects
  • Neurons / ultrastructure*
  • Receptor Cross-Talk


  • Cysteine Proteinase Inhibitors
  • Leupeptins
  • Caspase 3
  • leupeptin