Dantrolene normalizes heightened Ca2+ influx in activated T cells from the familial Alzheimer's disease TgF344-AD rats

Aim

Dysregulation of the peripheral immune response contributes to Alzheimer's disease pathogenesis. Dantrolene, a negative allosteric modulator of ryanodine receptor types 1 and 3, reduces neurodegeneration in Alzheimer's disease animal models by an unclear mechanism. Given that Alzheimer's disease causative mutations in amyloid precursor and presenilin proteins interfere with intracellular Ca²⁺ signaling in neurons, we tested the hypotheses that these mutations may impair Ca²⁺ signaling in T lymphocytes and that dantrolene can repair this defect.

Methods

We explored cytosolic Ca²⁺ dynamics and effects of dantrolene sodium in resting and activated splenic T cells derived from adult transgenic TgF344-AD rats expressing mutant human "Swedish" amyloid precursor (APPsw) and presenilin 1 lacking exon 9 (PS1Δ9) proteins, and in control wild-type rats.

Results

We found no differences in the cytosolic Ca²⁺ signaling between resting T cells from TgF344-AD and control rats. In contrast, amplitudes of caffeine-triggered calcium transients and store-operated Ca²⁺ entry were significantly larger in activated TgF344-AD rat T cells relative to wild-type rat T cells. Preincubation with dantrolene sodium reduced the amplitude and the rate of Ca²⁺ influx in activated TgF344-AD rat T cells in the absence of store refilling and after dissipation of inner mitochondrial membrane potential, indicating that it does not involve Ca²⁺ release via ryanodine receptors or mitochondrial Ca²⁺ uptake.

Conclusions

Expression of Alzheimer's disease risk genes upregulates the store-operated Ca²⁺ entry in T cells, which may alter peripheral immune responses and exacerbate Alzheimer's disease pathogenesis. We speculate that dantrolene's neuroprotective effect in Alzheimer's disease animal models may be due to its normalization of the peripheral T cells' Ca²⁺ signaling and functions.