Neuronal apoptosis and autophagy cross talk in aging PS/APP mice, a model of Alzheimer's disease.
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.
Yang
Dun-Sheng
DS
Center for Dementia Research, Nathan Kline Institute, New York University School of Medicine, 140 Old Orangeburg Rd., Bldg. 39, Orangeburg, NY 10962, USA. dyang@nki.rfmh.org
Kumar
Asok
A
Stavrides
Philip
P
Peterson
Jesse
J
Peterhoff
Corrine M
CM
Pawlik
Monika
M
Levy
Efrat
E
Cataldo
Anne M
AM
Nixon
Ralph A
RA
D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000502:physiology*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000008:administration & dosage; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D007276:Injections, Intraventricular; D007976:Leupeptins / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure*; D020239:Receptor Cross-Talk
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D053148:Caspase 3; C032854:leupeptin