Department of Neurobiology at the Barrow Neurological Institute and St. Joseph’s Hospital and Medical Center

	ABSTRACT

 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.

	INDEX

• Jie Wu. (2023) Aged APP AD Mice Demonstrate Spontaneous Ca2+ Oscillations of Pancreatic Acinar Cells: First Evidence of Amyloid pores in AD Model, in Editor M. Baudry (Ed.), IABS Forum 2023 (p. 10). International Association of Biomedical Sciences (IABS). DOI: 10.59566/iabs.2023.p010