The enigma of cell death in neurodegenerative disorders
Progressive cell loss in specific neuronal populations is the pathological hallmark of neurodegenerative diseases, but its mechanisms remain unresolved. Apoptotic cell death has been implicated as a major mechanism in Alzheimer disease (AD), Parkinson dis
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I Ludwig Boltzmann Institute of Clinical Neurobiology, Vienna, Au stria Department of Neuroimmunology, Brain Research Inst itut e, Un iversity of Vienna School of Medicine, Vienna, Austria. Present address: Department of Neuropathology, Charite, Berlin, Germany
Summary. Progressive cell loss in specific neuronal populations is the pathological hallmark of neurodegenerative diseases , but its mechanisms remain unresolved. Apoptotic cell death has been implicated as a major mechanism in Alzheimer disease (AD), Parkinson disease (PD) and other neurodegenerative disorders. However, DNA fragmentation in human brain as a sign of neuronal cell injury is too frequent to account for the continuous loss in these slowly progressive disea ses. In a series of autopsy confirmed cases of AD , PD , related disorders, and age-matched controls, DNA fragmentation using the TUNEL method, an array of apoptosis-related proteins (ARP), proto-oncogenes, and activated caspase-3, the key enzyme of late-stage apoptosis, were examined. In AD , a considerable number of hippocampal neurons and glial cells showed DNA fragmentation with a 3- to 6-fold increase related to neurofibrillary tangles and amyloid deposits, but only 1 in 2.600 to 5.600 neurons displayed apoptotic morphology and cytoplasmic immunoreactivity for activated caspase-3, whereas no neurons were labeled in agematched controls. caspase-3 immunoreactivity was seen in granules of cells with granulovacuolar degeneration, in around 25% co-localized with early cytoplasmic deposition of tau-protein. In progressive supranuclear palsy, only single neurons and several oligodendrocytes in brainstem, some with taudeposits, were TUNEL-positive and expressed both ARPs and activated caspase-3. In PD , dementia with Lewy bodies, multisystem atrophy (MSA), and corticobasal degeneration, TUNEL-positivity and expression of ARPs or activated caspase-3 were only seen in microglia and oligodendrocytes with cytoplasmic inclusions , but not in neurons. These data pro vide evidence for extremely rare apoptotic neuronal death in AD and PSP compatible with the progression of neuronal degeneration in these chronic disease s. Apoptosis mainly involves reactive microglia and oligodendroglia, the latter often involved by deposits of insoluble fibrillary proteins, while alternative mechanisms of neuronal death may occur . Susceptible cell populations in a proapoptotic environment show increased vulnerability towards metabolic or other noxious factors , with autophagy as a possible protective mechanism in early stages of programmed cell death. The intracellular cascade leading to cell death still awaits elucidation.
P. Riederer et al. (eds.), Advances in Research on Neurodegeneration © Springer-Verlag Wien 2000
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K. A. Jellinger and Ch. Stadelmann
Introduction
Neurodegenerative disorders such as Alzheimer disease (AD), the most common cause of dementia in advanced age, and Parkinson disease (PD), the most frequent movement disorder, are morphologically characterized by progressive cell loss in specific
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