Lymphocytes and neutrophils as peripheral models to study the effect of beta-amyloid on cellular calcium signalling in Alzheimer's disease

According to the calcium hypothesis of brain aging, disturbances of free intracellular calcium homeostasis ([Ca2+]i) play a key role in pathology of Alzheimer's disease (AD). Recent data from neuronal tissue culture support the contribution of the beta-amyloid peptide (beta A) to neurodegeneration in AD, probably by disruption of the intracellular Ca2+ regulation. On the basis of this premise, we used peripheral blood cells to examine the role of beta A on Ca2+ signalling, not only to obtain an experimental approach to investigate these effects of beta A in man, but also to search for AD-specific alterations of the effects of beta A on Ca2+ signalling. This approach is based on observations indicating that the phytohemagglutinin (PHA)-induced Ca2+ response in circulating human lymphocytes of healthy volunteers is affected by beta A and its fragment 25-35 in a fashion similar to its effects on central neurons, whereas we found no effect of beta A on receptor-activated Ca2+ response in neutrophils. Therefore, we used human blood lymphocytes as peripheral model systems to search directly for AD-related abnormalities of Ca2+ regulation, for alterations of beta A effects on Ca2+ signalling and on membrane fluidity, and for possible changes of potassium channels. In accordance with our data in neutrophils, we were unable to identify any relevant change of the PHA-induced Ca2+ elevations in lymphocytes, which is not supporting the assumption of general alterations of cellular Ca2+ regulation in AD. On the other hand, the amplifying effect of beta A on Ca2+ signalling was significantly reduced in lymphocytes from AD patients. Moreover, Ca2+ responses to beta A25-35 were not different between early- and late-onset AD patients. Our findings indicate that the sensitivity of the lymphocyte for the effects of beta A is reduced in a high percentage of patients with probable or possible AD. As possible explanation we observed a similar reduction of the sensitivity of the ly