Dysregulation of the peripheral immune response contributes to Alzheimer’s disease pathogenesis. Structural changes were reported in the spleens of rodents carrying familial Alzheimer's disease mutations. However, whether the expression of Alzheimer's disease risk genes affects the functions of peripheral immune cells remains unknown. Because elevation in the intracellular Ca 2+ concentration drives many vital functions in T lymphocytes, we explored the cytosolic Ca 2+ dynamics in splenic T cells derived from adult transgenic TgF344-AD rats expressing mutant human “Swedish” amyloid precursor protein (APPsw) and presenilin 1 lacking exon 9 (PS1Δ9) proteins, as well as in control wild-type rats. Isolated T cells were activated ex vivo with mitogenic lectin phytohemagglutinin P. Comparison of changes in cytosolic Ca 2+ concentration detected with Fura-2, in response to application of caffeine or blockade of a sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA), revealed no differences in the cytosolic Ca 2+ signaling between resting T cells from TgF344-AD and wild-type rats. In contrast, amplitudes of caffeine-triggered Ca 2+ transients and store-operated Ca 2+ entry were upregulated in activated TgF344-AD T cells relative to wild-type T cells. Preincubation with a ryanodine receptor type 1 and 3 antagonist, dantrolene sodium, reduced the amplitude and the rate of Ca 2+ influx in activated TgF344-AD rat T cells in the absence of Ca 2+ re-uptake into endoplasmic reticulum by SERCA and after suppression of mitochondrial Ca 2+ uptake. We concluded that expression of Alzheimer's disease risk genes upregulates the store-operated Ca 2+ entry in T cells, which may alter peripheral immune responses and exacerbate Alzheimer's disease pathogenesis. We speculate that the previously described neuroprotective effect of dantrolene in Alzheimer's disease animal models may be due to its normalization of peripheral T cell Ca 2+ signaling and functions.
Uppal et al. (Sun,) studied this question.