Caspases In Neuronal Apoptosis And Neurodegenerative Disorders

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Three major lines of evidence support roles for caspases in neuronal apoptosis that occurs during normal development of the nervous system and in neurodegenerative disorders. The first line of evidence is that caspase activation is increased in neurons prior to their demise during development of the nervous system in mammals, and in humans with neurodegenerative disorders. The second line of evidence is that caspase activation occurs prior to, and in association with, neuronal death in cell culture and in vivo models of neurodegenerative disorders. The third line of evidence is that caspase inhibitors or genetic "knockout" of caspases prevent neuronal death. Caspase activity is typically assessed by determining whether caspase substrates are cleaved, and by employing "reporter" caspase substrates in either in vitro or in situ assays101102. Analyses of neuronal populations in which programmed cell death occurs during development have revealed evidence for caspase activation. For example, caspase-3 is activated in CNS neurons that undergo apoptosis in developing mice103.

Examination of tissue sections from brains of Alzheimer's patients immunostained with an antibody that specifically recognizes activated caspase-3 reveals evidence for caspase activation in vulnerable neuronal populations in the hippocampus and cerebral cortex. Masliah et al.104 stained brain sections from Alzheimer's disease and age-matched control patients with antibodies against activated caspase-3 and reported that, compared to age-matched controls, Alzheimer's patients exhibited greatly increased numbers of neurons with caspase-3 immunoreactivity. Chan and coworkers102 showed that overall levels of activated caspase- 1 activity are increased in hippocampal tissue from Alzheimer patients and that many neurons exhibit immunoreactivity with an antibody against activated caspase-3. The latter study also provided evidence for caspase-mediated degradation of the AMPA-type glutamate receptor subunits in Alzheimer's brain tissue and in cultured neurons exposed to amyloid b-peptide. Immunostaining of brain sections from Alzheimer's disease and Down Syndrome patients using an antibody against activated caspases revealed labeling of approximately 0.02 -0.1 % of neurons, while no neurons were labeled in tissue from control patients105.

The involvement of individual caspases in programmed death of neurons has been studied in mice using caspase inhibitors and gene-targeting methods to specifically disrupt a caspase gene. Overexpression of the caspase-1 inhibitor crmA prevents programmed cell death of dorsal root ganglion neurons in the developing chick60. Examination of caspase knockout mice has revealed interesting tissue-specific roles for individual caspases106 107 108 50. For example, mice lacking caspase-3 have severe defects in nervous system development, but no apparent abnormalities in apoptosis of lymphocytes. Caspase-3 knockout mice die within five weeks of birth and display profound abnormalities in the cerebral cortex and forebrain owing to failed apoptosis in the proliferative neuroepithelium106 109. Caspase-9 knockout mice exhibit a phenotype similar to that of caspase 3-deficient mice, but die at a younger age. Cells lacking caspase-9 are highly resistant to apoptosis induced by radiation, but are susceptible to death induced by Fas ligation107. Mice lacking caspase-8 suffer early lethality and are resistant to Fas- and TNF-induced cell death, indicating that despite the association of these receptors with caspase 10, they depend on caspase 8 for cell death induction in vivo110. Caspase-1 knockout mice have no major defects in apoptosis and are developmentally normal, indicating that this caspase does not play a critical role in cell death during development111. Nevertheless, mice lacking caspase-1 do have a defect in interleukin-lb (IL- 1b) processing in response to lipopolysaccharide and are resistant to endotoxic shock112. Moreover, the production of inflammatory cytokines (TNF, IL-Ib and IL-6) is impaired consistent with a role for caspase-1 in inflammation113. Thus, caspase activation does not necessarily result in apoptosis, as cytokine processing is observed during a normal immune response without apoptosis of the secreting cells114.

Studies of experimental models of neurodegenerative disorders have provided further evidence for a causal role for caspase activation in the neurodegenerative process (Fig. 2). Exposure of cultured hippocampal neurons to amyloid P-peptide induces caspase-3 activation, and treatment of the neurons with caspase inhibitors protects them against apoptosis induced by amyloid P-peptide115116. When expressed in knockin mice, mutations in presenilin-1 that cause early-onset inherited Alzheimer's disease result in increased neuronal vulnerability to apoptosis which is associated with increased caspase activation117.

Figure 2. Roles of caspases and calpains in neuronal degeneration in Alzheimer's disease. See text for discussion. Ab, amyloid b-peptide; ApoE, apolipoprotein E; APP, amyloid precursor protein; ER, endoplasmic reticulum; PAW, poly-ADP-ribose polymerase; ROS, reactive oxygen species; RyR, ryanodine receptor; VDCC, voltage-dependent calcium channel.

Figure 2. Roles of caspases and calpains in neuronal degeneration in Alzheimer's disease. See text for discussion. Ab, amyloid b-peptide; ApoE, apolipoprotein E; APP, amyloid precursor protein; ER, endoplasmic reticulum; PAW, poly-ADP-ribose polymerase; ROS, reactive oxygen species; RyR, ryanodine receptor; VDCC, voltage-dependent calcium channel.

Transgenic mice expressing exon 1 of the huntingin gene with an expanded polyglutamine repeat, a model of Huntington's disease, exhibit increased caspase- 1 activation in association with progressive neurodegeneration. Expression of a dominant negative caspase-1 mutant delays development of neurodegenerative changes and motor dysfunction118. Degeneration of dopaminergic neurons in the substantia nigra of rats induced by 6-hydroxydopamine, a model of Parkinson's disease, is greatly reduced in animals pretreated with the caspase inhibitor zVAD-fmk119.

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