Introduction: Targeted Modulation of Neuronal Apoptosis: A Double‐Edged Sword?

Apoptosis is one of the most exciting and intensely investigated areas of biology and medicine today. Apoptosis was originally defined by a series of distinct morphological and biochemical events suggesting the presence of a common execution machinery of cell death in different cells. Condensation and fragmentation of nuclear chromatin, compaction of cytoplasmic organelles, a decrease in cell volume and alterations to the plasma membrane are typical features of apoptosis. The latter results in the recognition and phagocytosis of apoptotic cells. The nuclear alterations are often associated with internucleosomal cleavage of DNA, recognized as DNA laddering on conventional agarose gel electrophoresis. Internucleosomal cleavage of DNA is a relatively late event in the apoptotic process. Apoptosis has first been recognized during vertebrate development as part of a natural process to remove superfluous or no-more-needed cells, including removal of neurons during normal development of the brain. It is generally accepted that neurons are generated in excess so that they may compete for contacts with their cellular partners and thus adjust their numbers so as to provide appropriate innervation of their targets. It has since become a common theme that aberrant neuronal apoptosis may also occur as a feature of disease processes of the adult brain. Consequently, it has been suggested that blocking apoptosis may be a treatment strategy for several acute or chronic neurodegenerative diseases of the adult brain (7, 9). This series of reviews is based on a Symposium on Neuronal Apoptosis which took place in Tübingen, Germany, August 5-7, 1999. Invited speakers were: Adriano Aguzzi, Mathias Bähr, M. Flint Beal, Paolo Bernardi, Patrik Brundin, Valina Dawson, Alvaro Estevez, Lloyd Greene, Erich Gulbins, David Kaplan, Stuart Lipton, Pedro Lowenstein, Jean-Claude Martinou, Mark Mattson, Michael A. Moskowitz, Donald W. Nicholson, Henry Paulson, George Perry, Jochen H.M. Prehn, George Robertson and Michael Weller. Major topics of the symposium included (1) morphologic concepts and the genetic regulation of the apoptotic process, (2) signal transduction and mitochondria, (3) the role of caspases in neuronal apoptosis, and (4) apoptosis in acute and chronic neurological disease. The following articles primarily focus on (i) the mechanisms of apoptosis in differentiated neurons in vitro and in vivo, (ii) whether neuronal apoptosis occurs in models of acute and chronic neurological disorders and (iii) whether it may be beneficial to block neuronal apoptosis in neurodegenerative diseases. During the last decade, the genetic regulation and the biochemical pathways of apoptosis have been extensively investigated. The core components of the machinery resulting in apoptotic cell death were first described in the nematode, Caenorhabditis elegans. Three cell death genes were identified, the pro-apoptotic (deathpromoting) genes ced-3 and ced-4, and the anti-apoptotic gene, ced-9. This machinery is highly conserved in vertebrates. Mammalian homologs are the caspase family (ced-3), the apoptosis protein activating factor-1 (Apaf-1, ced-4) and the Bcl-2 family (ced-9). Caspases, a family of at least 14 enzymes with specific proteolytic properties, are considered to be the main executioners of apoptosis (10). Inhibition of caspases by specific peptide or protein inhibitors or inhibition of caspase activation, e.g. by enforced BCL-2 expression, prevents apoptosis. Brain Pathology 10: 273-275(2000)