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Gene-Regulated Cell Death: Apoptosis

Apoptosis can be differentiated from necrosis based on differences in their pathogenesis, cell reactions, and morphologic features. Apoptosis is the programmed death of a cell as regulated by specific death genes (for review see Clarke 1998). It initiates a delayed secondary death of neurons in response to environmental changes, deficient metabolic and trophic supply, and changed gene transcription. During apoptosis, the integrity of mitochondria is compromised and various pro-apoptotic proteins are released into the cytoplasm. This results in activation of caspases, proteases that orchestrate the death of the cell (Waterhouse 2003). Apoptosis requires active protein synthesis (McIntosh et al. 1998; Raghupathi et al. 2000). A single cell can undergo a switch between the two types of cell death based on several pathways (McConkey 1998; Fiskum et al. 1999; see also Leist et al. 1990) (for further informations, see p. 620).

The characteristic morphology of apoptosis exhibits cleavage of the internucleosomal chroma-tin that can be identified in situ using the terminal

Fig. 4.17a-d. Cortical necrosis, i.e., laminated necrosis. a Mac- cerebellum the necrosis (c) is totally replaced (d) by a distinct roscopy of long-time survival of cortical necrosis which is asso- gliosis (b-d H&E; magnification b, c X100; d X200) ciated with a complete cortical (cystic) necrosis (b) while in the

Fig. 4.17a-d. Cortical necrosis, i.e., laminated necrosis. a Mac- cerebellum the necrosis (c) is totally replaced (d) by a distinct roscopy of long-time survival of cortical necrosis which is asso- gliosis (b-d H&E; magnification b, c X100; d X200) ciated with a complete cortical (cystic) necrosis (b) while in the

Fig. 4.16a, b. Activated astrocytes along the border zone of necrosis. a Astrocytic reaction in the cortex and (b) in the white matter (GFAP reactivity; magnification a X1,000, b X500)
Fig. 4.18a-d. Global ischemia leads to cystic necrosis of the ba- long survival time after cardiac arrest demonstrating necrosis of sal ganglia. Two cases are demonstrated: (a, c) and (b, d) with a the pallidum (a, b: MRI)

Fig. 4.19a-d. Neuronal loss in the hippocampal area (CA1 sec- c the lost neurons are replaced by CD68 reactive microglia and tor) and glial reaction (see also Fig. 14.14, p. 309). a The Ammon's d in cases of longer survival time, by astrocytes (a, b MAP2 reac-

horn CA1 sector is characterized by a distinct loss of nerve cells; tivity; c CD68 reactivity; d GFAP reactivity; magnification a x50;

b by high magnification of the marked sector (see a) intact neu- b, c, d x500) rons are seen in the center as well as a bilateral loss of neurons;

Fig. 4.19a-d. Neuronal loss in the hippocampal area (CA1 sec- c the lost neurons are replaced by CD68 reactive microglia and tor) and glial reaction (see also Fig. 14.14, p. 309). a The Ammon's d in cases of longer survival time, by astrocytes (a, b MAP2 reac-

horn CA1 sector is characterized by a distinct loss of nerve cells; tivity; c CD68 reactivity; d GFAP reactivity; magnification a x50;

b by high magnification of the marked sector (see a) intact neu- b, c, d x500) rons are seen in the center as well as a bilateral loss of neurons;

Fig. 4.20a-c. Coagulation necrosis. a Necrotic area is limited by a spongious border zone (arrows); b, c fragments of intact tissue components are visible and not phagocytosed (a H&E; b, c van Gieson stain; magnification a x5; b X100; c X200)

deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) method (Gavrieli et al. 1992). Apoptosis causes pyknosis of the nucleus and condensation and shrinkage of the cell body. As it progresses, budding and karyorrhexis occur, and ultimately a breakup into clusters of apoptotic bodies (Majno and Joris 1995).

The time course of apoptosis following a traumatic event is as follows: about 4 h after a traumatic event, apoptosis begins, and remains demonstrable for about 3 days (Yakovlev and Faden 1997).

Three major factors are known to participate in the apoptotic cascade of "delayed" neuronal death

(for review Kermer et al. 1999; see also Huppertz et al. 1999):

1. Immediate early gene transcription factors (c-jun, jun-B, jun-D, c-fos, AP-1, ATF, NF-kB)

2. Proteases (calpains, caspases)

3. Glutamate-mediated toxicity (free radicals, pro-tein-kinases, Ca2+ homeostasis, second messenger systems)

The death-inducing activity of the Bax, Bad, Bid, Bcl-xs family members is thought by Raghupathi et al. (2000) to be in dynamic equilibrium with their survival-promoting cognates Bcl-2, Bcl-xL. Shifts in the protective intracellular Bcl-2-family-protein levels can tilt the balance toward cell death by activating the death-inducing cysteine proteases, caspases (Thornberry and Lazebnik 1998).

The death of single cells releases insufficient quantities of chemoattractants to allow effective concentrations of molecular species to reach the vascular endothelium. For this reason a genuine cell reaction does not occur. Neighboring cells that are not professional phagocytes cannibalize the cell debris in a process specific to apoptosis (Majno and Joris 1995). In inflammatory diseases, an essential factor in the resolution of the inflammatory attack is the clearance of apoptotic leukocytes by tissue-specific phagocytes (Platt et al. 1998). This process has been termed the "safe, phagocytic clearance of dying, yet intact leukocytes undergoing apoptosis" involving rapid recognition, uptake, and degradation.

Microglial cells were recently shown to be capable of protecting neurons, cerebellar granule neurons in particular, from apoptosis (Polazzi et al. 2001): molecules are released by apoptotic neurons that enable the anti-apoptotic activity of microglia. In vitro, normal microglia release molecules capable of rescuing neurons from apoptotic death.

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