Published online before print August 7, 2008

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(American Journal of Pathology. 2008;173:665-681.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071176

Neuronal Apoptosis and Autophagy Cross Talk in Aging PS/APP Mice, a Model of Alzheimer’s Disease

Dun-Sheng Yang^*, Asok Kumar^*, Philip Stavrides^*, Jesse Peterson, Corrine M. Peterhoff^*, Monika Pawlik^*, Efrat Levy^*, Anne M. Cataldo and Ralph A. Nixon^*¶

From the Center for Dementia Research,^* Nathan S. Kline Institute, Orangeburg, New York; the Departments of Psychiatry, Cell Biology,^¶ and Pharmacology, New York University School of Medicine, New York, New York; and the Mailman Research Center, McLean Hospital, Harvard University, Belmont, Massachusetts

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 -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.