Many sympathetic and sensory neurons depend on a supply of nerve growth factor (NGF) from their targets during development, and neurons that fail to obtain sufficient NGF die by apoptosis. Here we show that tumor necrosis factor alpha (TNFalpha) is involved in bringing about the death of NGF-deprived neurons. Function-blocking antibodies against either TNFalpha or TNF receptor 1 (TNFR1) rescued many sympathetic and sensory neurons following NGF deprivation in vitro. Fewer sympathetic and sensory neurons died during the phase of naturally occurring neuronal death in TNF-deficient embryos, and neurons from these embryos survived in culture better than wild-type neurons. These neurons coexpress TNFalpha and TNFR1 during this stage of development, suggesting that TNFalpha acts by an autocrine loop.

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Alzheimer patients have increased levels of both the 42 amyloid-beta-peptide (Abeta) and the amyloid binding alcohol dehydrogenase (ABAD), which is an intracellular binding site for Abeta. The overexpression of Abeta and ABAD in transgenic mice has shown that the binding of Abeta to ABAD results in amplified neuronal stress and impairment of learning and memory. From a proteomic analysis of the brains from these animals, we have identified for the first time that the protein endophilin I increases in Alzheimer diseased brain. The increase in endophilin I levels in neurons is linked to an increase in the activation of the stress kinase c-Jun N-terminal kinase with the subsequent death of the neurons. We also demonstrate in living animals that the expression level of endophilin I is an indicator for the interaction of ABAD and Abeta as its expression levels return to normal if this interaction is perturbed. Therefore this identifies endophilin I as a new indicator of the progression of Alzheimer disease.

Neurotrophins mediate their effects by binding to members of the Trk family of receptor tyrosine kinases and the neurotrophin receptor p75 [1]. Whereas Trks are essential for the trophic effects of neurotrophins [1], p75 has distinct functions in different cells. For example, it enhances the survival response of certain neurons to nerve growth factor (NGF) [2], but mediates a cytotoxic response to NGF in certain other cell types and neurons [3] [4] [5] [6]. We investigated whether the p75-mediated responses to NGF can be modulated through the activation of different signalling pathways in the same neurons. Neurons of the embryonic trigeminal mesencephalic nucleus (TMN) are supported in culture by brain-derived neurotrophic factor (BDNF) and an unrelated neurotrophic factor, ciliary neurotrophic factor (CNTF), but not by NGF [7] [8] [9]. We found that NGF killed TMN neurons that were grown in the presence of CNTF; this effect of NGF was inhibited by anti-p75 antibodies and therefore occurred via a p75-dependent mechanism. NGF did not affect the survival of neurons grown in the presence of BDNF, and very low concentrations of BDNF inhibited NGF cytotoxicity. These results indicate that the activation of different signalling pathways in TMN neurons influences their susceptibility to p75-mediated NGF cytotoxicity.

The L1 family of CAMs (cell adhesion molecules) has long aroused the interest of researchers, but primarily the extracellular interactions of these proteins have been elucidated. More recently, attention has turned to the intracellular signalling potentiated by transmembrane proteins and the cytoplasmic proteins with which they can interact. The present review brings up to date the current body of published knowledge for the intracellular interactions of L1-CAM family proteins and the potential importance of these interactions for the mechanisms of L1-CAM action.