Aged APP AD Mice Demonstrate Spontaneous Ca2+ Oscillations of Pancreatic Acinar Cells: First Evidence of Amyloid pores in AD Model

Alzheimer’s disease (AD), the primary cause of dementia, involves the accumulation of beta-amyloid peptides (Aβ) in brain plaques. Aβ’s precise toxic mechanisms remain unclear. The Aβ channel hypothesis suggests Aβ forms Ca2+-permeable channels in cell membranes, possibly leading to Ca2+ signal disruption and neurodegeneration. Detecting Aβ-formed Ca2+channels in native cells of AD model animals is a key question. In our study, we identified Aβ-formed Ca2+ channels in aged amyloid precursor protein (APP) transgenic AD mice. Measuring intracellular Ca2+ signals in mouse pancreatic acinar cells, we observed spontaneous Ca2+ oscillations following whole-cell configuration formation. Ca2+ influx triggered these oscillations, as external Ca2+ removal halted them. Notably, we couldn’t replicate these oscillations in pancreatic acinar cells from age-matched wildtype (WT) mice or younger APP mice. Given the absence of voltage-gated Ca2+ channels in pancreatic acinar cells, external Ca2+influx-triggered oscillations may involve Aβ-formed Ca2+-permeable channels. Supporting this, we found Aβ plaques in pancreatic sections from aged APP mice, and in adult WT mice’s pancreatic acinar cells, Aβ application produced Ca2+ oscillations dependent on external Ca2+. Furthermore, adding oligomer Aβ1-42 into patch pipette solution enabled Aβ-perforated channel measurement, and fluorescent-tagged Aβ1-42 in primary hippocampal cultures revealed Aβ spots within cells. This study provides experimental evidence that Aβ can form Ca2+ permeable channels in pancreatic acinar cells in aged APP AD model mice, shedding light on novel mechanisms for understanding altered Ca2+ homeostasis and neurotoxicity in AD pathogenesis.