transduction pathways in neurons as early mediators of neuron dysfunction and subsequent death.

Signal Transduction Pathways May Be Compromised Much Sooner Than Degeneration Develops

One of the components that is critical in signal transduction is CREB (cyclic AMP response element binding protein), a molecule that mediates a plethora of responses involving gene transcription. Briefly, the pathway leading to the activation of CREB starts with an increase in Ca2+ or cAMP, which leads to the activation of calcium calmodulin-dependent (CAM) Kinase IV or cAMP-dependent protein kinase (protein kinase A). CAM Kinase IV or protein kinase A translocates into the nucleus and phosphorylates CREB, thereby activating this protein. Once CREB is phosphorylated, it can bind to cyclic AMP response element (CRE) in the promoter region of specific genes and increase transcription, leading to increased RNA and protein levels. One of these proteins is brain-derived neurotrophic factor (BDNF), which promotes neuron survival and plasticity (Cellerino et al., 1996; Galuske et al., 1996; Ma et al., 1998). As the actions of CREB become more elucidated, it is becoming apparent that CREB is functionally important for neuroplasticity (Ahn et al., 1999; Bailey et al., 1996; Glazewski et al., 1999; Schultz et al., 1999; Segal et al., 1998).

Recent data suggest that transgenic mice that do not express CREB or mice treated with antisense mRNA to CREB show impaired long-term potentiation, a physiological mechanism thought to underlie short-term memory (Glazewski et al., 1999; Schultz et al., 1999). A recent study also indicates that brains of humans diagnosed with Alzheimer's disease have decreased levels of phosphorylated CREB (pCREB) (Yamamoto-Sasaki et al., 1999), and it is hypothesized that this decline may have a role in memory decrements. While a direct mechanism or causal effect of declines in pCREB has not been established in normal aging in humans or animals, it is hypothesized that short-term memory deficits that occur as mild cognitive impairment in humans or as memory impairments in individual old canines may be a consequence of neuronal dysfunction associated with decreased phosphorylation of CREB signal transduction mechanisms or other transcription factors.

This leads to the question of whether a similar series of events occurs with sublethal exposures to Aβ, as would be expected in the early initiation phase. Depolarization of cells, as would occur in vivo with long-term potentiation, induces the phosphorylation of CREB. However, in the presence of sub-threshold levels of Aβ, there is a significant reduction in pCREB (Tong et al., in press). One interpretation of these results is that transcriptional activation by CREB could be compromised in dysfunctional neurons prior to overt cell death. If the neuron can reverse dysfunction, such as a diminished CREB



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