Calcineurin as a Pivotal Ca²⁺-Sensitive Switching Element in Biological Responses: Implications for the Regulation of Tau Phosphorylation in Alzheimer’s Disease

Summary

Reversible protein phosphorylation provides a key strategy for biological control, as it allows the informational status of a cell to be modified dynamically en route to changes in cellular response. A hallmark feature of Alzheimer’s disease is the presence of “hyperphosphorylated” forms of the microtubule-associated protein, tau, in paired helical filaments. Although the relationship of this biochemical abnormality to disease etiology and pathology is unknown, it may reflect aberrant cytoskeletal regulation. One hypothesis to explain tau hyperphosphorylation is a dysregulation of phosphoprotein phosphatases. Consistent with this idea, incubation of human brain tissue slices with the phosphatase inhibitor okadaic acids leads to production of the characteristic tau epitope (Harris et al. 1993). Studies in vitro have shown that each of the three major serine-threonine phosphatases inhibited by okadaic acid (PP-1, PP-2A, PP-2B) can dephosphorylate tau, with PP-2A having the highest activity. Recently, studies carried out with cerebellar macroneuron model cultures showed that the protein phosphatase, calcineurin (PP-2B), is intimately associated with developing microtubule/ microfilament structures; thus, calcineurin may have “privileged access” to substrates that modulate the cytoskeleton. Provocatively in this study, specific calcineurin inhibitors blocked elements of neuronal “decision-making” (axonal determination) while, at the same time, causing tau hyperphosphorylation (Ferreira et al. 1993). These data suggest that this Ca²⁺-sensitive phosphatase may play a role in regulating tau function in vivo.

Calcineurin is uniquely suited to influence signal transduction events because it is under the direct control of the second messenger, Ca²⁺. However, because it shows rather narrow substrate specificity in vitro, it seems likely that it acts on relatively few target proteins which may affect broader signaling cascades. This appears to be true in skeletal muscle, where calcineurin mediates a reversal of epinephrine-induced glycogen breakdown by dephosphorylating an inhibitor of the broad specificity protein phosphatase (PP-1). A related scenario may occur in T cell lymphokine responses, where multiple trans-acting factors are activated through events controlled by calcineurin, although the details of these events are not clear. Similarly, the regulation of tau dephosphorylation described above may also be indirect, operating via pathways that are tightly linked to calcineurin.