al., 1997; Loddick et al., 1998). Venters et al. found that TNRα significantly reduces the ability of IGF-I to promote survival in cerebellar granule neurons. These investigators proceeded to show that TNFα inhibits the ability of IGF-I to initiate tyrosine phosphorylation of the insulin receptor substrate 2 (IRS-2), thereby blocking the activation of downstream P13-kinase. Thus diseases of the central nervous system that have an inflammatory component involving TNFα, such as multiple sclerosis, AIDS-dementia complex, and Alzheimer's disease, may use intracellular cross-talk between TNFα and IGF-I receptors to inhibit survival signaling by IGF-I and perhaps other neurotrophic factors. Thus some molecules promote homeostasis by multiple mechanisms, and in diseases such as Alzheimer's disease, these mechanisms may be recruited into cascades that trigger disease progression.

In summary, neurons that experience pro-apoptotic insults appear to shut down key signal transduction pathways. At the single cell level, this is probably a wise strategy, because it potentially removes dysfunctional cells from the network. This would then, in turn, allow the fully functional cells to maintain brain function and possibly activate auxiliary use-dependent plasticity mechanisms (Figure B-2).

FIGURE B-2 Neurons subjected to sublethal pro-apoptotic insults may be deficient in their ability to regulate key signal transduction pathways serving functional plasticity. The presence of sublethal concentrations of B-amyloid results in an inability to phosphorylate CREB and thus control of essential transcriptional mechanisms. Thus these neurons are partially removed from the circuit (shaded cell).



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